CN108456178A - Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC-F）And its application - Google Patents

Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC-F）And its application Download PDF

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CN108456178A
CN108456178A CN201710089204.0A CN201710089204A CN108456178A CN 108456178 A CN108456178 A CN 108456178A CN 201710089204 A CN201710089204 A CN 201710089204A CN 108456178 A CN108456178 A CN 108456178A
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ligustrazine
derivative
trimethyl
hydroxybenzylalcohol
nmr
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张晨泽
王鹏龙
雷鹏程
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Abstract

Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC‑F）And its application.The present invention provides a kind of derivative that there is the ligustrazine of general formula structure 1 to replace p-Hydroxybenzylalcohol analog, such compound includes p-Hydroxybenzylalcohol analog parent nucleus and includes the substituent group of ligustrazine structure, general structure such as formula 1.Wherein R1Selected from OH, NH2, 3,5,6 trimethyl ligustrazine, 2 methylene oxygroup, 3,5,6 trimethyl ligustrazine, 2 formyloxy or 3, any one in 5,6 trimethyl ligustrazine, 2 formamido；R2Selected from H or OCH3In any one；R3Selected from OH, 3,5,6 trimethyl ligustrazine, 2 methylene or 3,5,6 trimethyl ligustrazine, 2 formoxyl any one, and R1‑R3In at least one include the substituent group of ligustrazine structure, n is 1 or 2.Application the present invention also provides the preparation method of the analog derivative and in preparing the damage for the treatment of brain neuroblastoma and its sequelae drug.

Description

Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative (LQC-F) it and its applies
Technical field
The present invention relates to a kind of ligustrazine derivants and its preparation method and application, specifically relate to a kind of ligustrazine para hydroxybenzene Methanol analog derivative, preparation method and its application in terms of neuroprotection, belong to medicinal chemistry art.
Background technology
Currently, the brain diseases such as headstroke, senile dementia, Parkinson's disease, brain trauma seriously endanger human health.Brain In the generation of disease, evolution, along with different degrees of neural cell injury, such as：Occur in ischemia apoplexy When, Oligemia causes the function of normal cell to change, and cerebral tissue is very sensitive to ischaemic, even if neuron is in short-term Between ischemic can also cause a series of event, eventually lead to the death of nerve cell.Therefore, currently above-mentioned serial encephalopathy is controlled Neuroprotective agents are widely used as a kind of important medicine in a line clinic in treatment.
The significant advantage that Chinese medicine compound prescription has with it in terms of the treatment of the above chronic complex disease, but because of Chinese medicine compound prescription The problems such as existence component is indefinite, and mechanism of action understanding is insufficient, makes its clinical application receive larger limitation.
Invention content
The present invention is guidance with Chinese medicine compound prescription compatibility theory and chemicals structure principle of hybridization, with chemical synthesis side Method filters out a kind of structural framework novelty, the specific ligustrazine substitution of activity from the structural modification object of hundreds of natural products P-Hydroxybenzylalcohol analog derivative (being named as LQC-F) has the research and development specific lead compound of structure Great research significance.
An object of the present invention is to provide a kind of compound L QC-F with general structure 1.
The second object of the present invention is to provide the preparation method of LQC-F.
The third object of the present invention is to provide LQC-F answering in preparing the damage for the treatment of brain neuroblastoma and its sequelae drug With.
The purpose of the present invention is what is be achieved through the following technical solutions：
A kind of ligustrazine substitution p-Hydroxybenzylalcohol analog derivative L QC-F, the compound include substitution para hydroxybenzene Methanol analog parent nucleus and the substituent group for including ligustrazine structure, general structure such as formula 1：
Formula 1
Wherein, R1Selected from-OH ,-NH2, 3,5,6- trimethyl ligustrazine -2- methylenes oxygroups, 3,5,6- trimethyl ligustrazines - 2- formyloxies or 3, any one in 5,6- trimethyl ligustrazine -2- formamidos；R2Selected from-H or-OCH3In it is arbitrary It is a kind of；R3Selected from-OH, 3,5,6- trimethyl ligustrazine -2- methylene or 3,5,6- trimethyl ligustrazine -2- formoxyls it is arbitrary One kind, and R1-R3In at least one include the substituent group of ligustrazine structure, n is 1 or 2.
Further, the p-Hydroxybenzylalcohol analog parent nucleus can be p-Hydroxybenzylalcohol, p-hydroxyphenylethanol, vanilla Any one in alcohol, para hydroxybenzene methylamine, Uteramin, Vanillylamine.
The compounds of this invention is numbered and concrete structure is shown in Table 1.
1 ligustrazine of table replaces the chemical constitution of p-Hydroxybenzylalcohol analog derivative L QC-F
The synthetic route of ligustrazine substitution p-Hydroxybenzylalcohol analog derivative of the present invention is as follows：
Route 1：The synthetic route of compound 1a-1c, 2a-2c.
R representative-H or-OCH in above-mentioned reaction3In any one；N is 1 or 2.
Reagent and condition：(i) DMF, K2CO3, 85 DEG C, 4h；(ii) DMF, NaH, 80 DEG C, 4h.
Route 2：The synthetic route of compound 3a-3c, 4a-4c, 5a-5c.
R representative-H or-OCH in above-mentioned reaction3In any one；N is 1 or 2.
Reagent and condition：(iii) DMF, EDCI, HOBt, DIPEA, r.t., 12h；(iv) DMF, K2CO3, 85 DEG C, 4h；(v) DMF, EDCI, DMAP, r.t., 12h.
Route 3：The synthetic route of compound 6a-6c, 7a-7c.
R representative-H or-OCH in above-mentioned reaction3In any one；N is 1 or 2.
Reagent and condition：(vi)CH2Cl2, EDCI, DMAP, r.t., 12h.
Intermediate 2- bromomethyls -3,5 in synthetic route of the present invention, 6- trimethylpyrazines (1), 2- carboxyls -3,5,6- tri- The specific preparation method of methylpyrazine (2) referring to《Ligustrazine formyloxy cinnamic acid derivative and the preparation method and application thereof, Application number：201210297075.1》With《A kind of drug and preparation method for treating ischemic brain damage apoplexy and its sequelae, Application number：201110062869.5).
The present invention also provides compound L QC-F to prepare the application in treating brain neuroblastoma damage medicine.Further, institute It includes headstroke, senile dementia, Parkinson's disease, brain trauma to state brain neuroblastoma damage disease.
Experimental example
Protective effect (Hu, the J. that LQC-A intends PC12 cells after differentiation ischemic injury models are observed using mtt assay； Zhao, T.Z.；Chu, W.H.；Luo, C.X.；Tang, W.H.；Yi, L.；Feng, H.Protective effects of 20- hydroxyecdysone on CoCl(2)-induced cell injury in PC12 cells.J.Cell Biochem.2010,111,1512-1521.)
1. material
1.1 experimental cell
PC12 cells PC12 (is purchased from Beijing consonance cell resource center)
1.2 experimental drug
(1a-1c, 2a-2c, 3a-3c, 4a-4c, 5a-5c, 6a-6c, 7a-7c (press embodiment 1-21 method systems to LQC-F It is standby)), liquid chromatogram (HPLC) analysis carries out Purity, and purity >=98% meets requirement of experiment.Powder-tight is stored in 4 well ℃.It is 2 × 10 with dmso solution4μM storing liquid it is spare.
Control drug：Ligustrazine.
2 methods
The culture of 2.1 PC12 cells
Cell growth is converged to 80-90% to be passed on, first by loose adherent cell with disposable dropper blowing gently It lays and comes (about under 20-30), collect the culture solution in the centrifuge tube of 15mL, remaining attached cell tryptic digestive juice Digestion, digestive juice are 0.05 pancreatin+0.02%EDTA.Cell dissociation state is observed under inverted microscope, waits for that space between cells increases, Major part is rounded, and after the termination digestion of 2mL complete mediums is added immediately, pats culture bottle, whole cells is made to take off wall, merge twice Containing cell culture fluid, 800rpm/min, 3min are centrifuged, abandons supernatant, cell is resuspended, complete medium is added, is seeded in new training It supports in bottle, sets 37 DEG C of constant temperature, 5%CO2, continue to cultivate in saturated humidity incubator.After PC12 cells are normally cultivated 72 hours, Culture medium (containing the dual anti-RPMI1640 of 5%HS+10%FBS+1%) is outwelled, 12- is cultivated with serum free medium (RPMI1640) It is 16 hours, spare.
The foundation of 2.2 PC12 cell differentiation models
Single cell suspensions are made in the PC12 cells of serum starvation, it is 7 × 10 to adjust cell density4A/mL, culture medium change For the RPMI1640 containing 10%FBS, plant into coated 96 orifice plates of PLL, per 100 μ L of hole.It is added to final concentration of S0ng/mL NGF In 96 orifice plates, continue to cultivate 36h.
The grouping and modeling of 2.3 PC12 cells
After cell differentiation, cell is divided into Normal group, NGF groups, administration group presses 3.75,7.5,15,30,60 respectively μm ol/L is that final concentration is added in 96 orifice plates, every group of 6 multiple holes, until after being cultivated for 24 hours in incubator, by final concentration of 200 μm of ol/ L CoCl2Solution is added in 96 orifice plates, is continued after cultivating 12h.It is separately added into the MTT (5mg/ml) of 20 μ L per hole, is incubated 4h OD values are measured at 490nm with microplate reader afterwards.
3 results
Ligustrazine series derivates under respective concentration to damage PC12 cell Proliferation calculation formula be：[OD490 (chemical combination Object)-OD490 (CoCl2)]/[OD490(NGF)-OD490(CoCl2)] × 100%；Finally the calculation formula of EC50 is：-pEC50 =log Cmax-log 2 × (∑ P-0.75+0.25Pmax+0.25Pmin), Cmax=maximum administration concentrations, five kinds of ∑ P=are dense The sum of lower damaging cells proliferation rate of degree, Pmax=maximums proliferation rate and Pmin=minimum proliferation rates.Concrete outcome is shown in Table 2.
Protection activities of 2 LQC-F of table to damaged nerve cells
The result shows that compound 1a, 1b, 1c, 2a, 2b, 2c, 3a, 3b, 3c, 4a, 4b, 4c, 5a, 5b, 5c, 6a, 6b, 6c, 7b is to CoCl2The protection activity of caused neural cell injury is higher than ligustrazine.Wherein, compound 2a and 2c are to CoCl2It is caused Neural cell injury has significant protection activity, EC50Respectively 1.66 and 1.07 μM.
Specific implementation mode
Embodiment 1
(4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) phenyl) methanol (1a)
260mg (2.1mmol) 4- hydroxy-benzyl alcohols, 358mg (2.1mmol) TMP-Cl, 290mg are sequentially added in round-bottomed bottle (2.1mmol) potassium carbonate；Add 20mLN, dinethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (petroleum ether) : V (acetone)=2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated aqueous sodium carbonate liquid measured Dispersion is extracted 3-4 times, combined ethyl acetate layer with equivalent ethyl acetate, is washed to neutral (a small amount of with saturated sodium-chloride water solution Repeatedly), anhydrous sodium sulfate is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 437.23mg.M.P.： 92.1-92.6 DEG C, yield 80.7%.
1H-NMR (500MHz, CDCl3)(ppm)：7.27 (d, j=8.3Hz, 2H, Ar-H), 6.97 (d, j=8.3Hz, 2H, Ar-H), 5.12 (s, 2H ,-CH 2), 4.60 (s, 2H ,-CH 2), 2.57 (s, 3H ,-CH 3), 2.51 (s, 6H ,-CH 3), 2.11 (s, 1H ,-OH).13C-NMR (125MHz, CDCl3)(ppm)：158.2,151.4,150.1,148.8,145.8,133.9,128.7, 115.0,70.0,64.9,21.7,21.5,20.7.HRMS (ESI) m/z：[M+H]+calcd for C15H19N2O2： 259.14465, found：259.14304.
Embodiment 2
2- (4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) phenyl) ethanol (1b)
276mg (2.0mmol) p-hydroxyphenylethanol, 341mg (2.0mmol) TMP-Cl, 276mg are sequentially added in round-bottomed bottle (2.0mmol) potassium carbonate；Add 20mLN, dinethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (petroleum ether) : V (acetone)=2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated aqueous sodium carbonate liquid measured Dispersion is extracted 3-4 times, combined ethyl acetate layer with equivalent ethyl acetate, is washed to neutral (a small amount of with saturated sodium-chloride water solution Repeatedly), anhydrous sodium sulfate is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 357.49mg.M.P.： 91.9-92.3 DEG C, yield 65.7%.
1H-NMR (500MHz, CDCl3)(ppm)：7.13 (d, j=8.3Hz, 2H, Ar-H), 6.95 (d, j=8.3Hz, 2H, Ar-H), 5.12 (s, 2H ,-CH 2), 3.83 (t, j=6.4Hz, 2H ,-CH 2), 2.80 (t, j=6.4Hz, 2H ,-CH 2), 2.58 (s, 3H ,-CH 3), 2.51 (s, 6H ,-CH 3), 1.61 (s, 1H ,-OH)13C-NMR (125MHz, CDCl3)(ppm)：157.4 151.3,150.1,148.8,145.9,131.0,130.1,115.1,70.1,63.9,38.4,21.7,21.4,20.6.HRMS (ESI)m/z：[M+H]+calcd for C16H21N2O2：273.16030.found：273.15878.
Embodiment 3
(3-methoxy-4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) phenyl) methanol (1c).
308mg (2.0mmol) vanillyl alcohol, 341mg (2.0mmol) TMP-Cl, 276mg are sequentially added in round-bottomed bottle (2.0mmol) potassium carbonate；Add 20mL n,N-Dimethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (oil Ether): V (acetone)=2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated sodium carbonate measured water-soluble Liquid disperses, and is extracted 3-4 times with equivalent ethyl acetate, combined ethyl acetate layer, is washed to neutral (few with saturated sodium-chloride water solution Amount is multiple), anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 323.65mg.M.P.： 112.7-113.2 DEG C, yield 56.2%.
1H-NMR (500MHz, CDCl3)(ppm)：6.97 (d, j=8.0Hz, 1H, Ar-H), 6.92 (s, 1H, Ar-H), 6.83 (d, j=8.0Hz, 1H, Ar-H), 5.17 (s, 2H ,-CH 2), 4.60 (s, 2H ,-CH 2), 3.83 (s, 3H ,-OCH 3), 2.60 (s, 3H ,-CH 3), 2.49 (s, 6H ,-CH 3), 2.12 (s, 1H ,-OH).13C-NMR (125MHz, CDCl3)(ppm)：151.2 150.3,150.1,148.6,147.6,145.9,134.8,119.3,114.5,110.0,71.2,65.3,56.0,21.7, 21.5,20.7.HRMS (ESI) m/z：[M+H]+calcd for C16H21N2O3：289.15520, found：289.15387.
Embodiment 4
2,3,5-trimethyl-6- (((4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) benzyl) oxy)methyl)pyrazine(2a).
It takes 248mg (2.0mmol) 4- hydroxy-benzyl alcohols to be placed in a reaction flask, 20mLN, N- dimethyl methyls is added into reaction bulb After amide stirring and dissolving, 96mg (4.0mmol) NaH is added, after stirring 0.5h, is added dropwise to 682mg (4.0mmol) TMP-Cl in room Temperature continues after being stirred to react 0.5h, the heating reaction 4h in 80 DEG C of oil baths.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- Should reaction substantially completely be stopped, cooling, filtering.Filtrate adds the saturated common salt of 5 times of amounts water-dispersed, and 3 are extracted with equivalent ethyl acetate It is secondary, combined ethyl acetate layer, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silicagel column point From white solid 503.21mg.M.P.：76.2-77.1 DEG C, yield 64.2%.
1H-NMR (500MHz, CDCl3)(ppm)：7.27 (d, j=8.5Hz, 2H, Ar-H), 6.97 (d, j=8.5Hz, 2H, Ar-H), 5.13 (s, 2H ,-CH 2), 4.60 (s, 2H ,-CH 2), 4.51 (s, 2H ,-CH 2), 2.57 (s, 3H ,-CH 3), 2.52 (s, 3H ,-CH 3), 2.51 (s, 6H ,-CH 3), 2.49 (s, 6H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：158.5 151.4,150.7,150.1,149.8,148.7,148.6,147.2,145.8,130.6,129.8,114.9,72.7 (- CH2), 71.6(-CH2), 70.1 (-CH2), 21.8 (-CH3), 21.7 (-CH3), 21.5 (-CH3), 21.5 (-CH3), 20.8 (-CH3), 20.6(-CH3).HRMS(ESI)m/z：[M+H]+calcd for C23H29N4O2：393.22905, found：393.22736.
Embodiment 5
2,3,5-trimethyl-6- ((4- (2- ((3,5,6-trimethylpyrazin-2-yl) methoxy) ethyl) phenoxy)methyl)pyrazine(2b).
It takes 276mg (2.0mmol) p-hydroxyphenylethanol to be placed in a reaction flask, 20mL N, N- diformazans is added into reaction bulb After base formamide stirring and dissolving, 96mg (4.0mmol) NaH is added, after stirring 0.5h, is added dropwise to 682mg (4.0mmol) TMP-Cl After room temperature continues to be stirred to react 0.5h, the heating reaction 4h in 80 DEG C of oil baths.TLC [V (petroleum ether): V (acetone)=2: 1] is examined It surveys reaction substantially completely, stops reaction, cooling, filtering.Filtrate adds the saturated common salt of 5 times of amounts water-dispersed, with equivalent ethyl acetate Extraction 3 times, combined ethyl acetate layer, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 497.96mg.M.P.：83.4-84.2 DEG C, yield 61.3%.
1H-NMR (500MHz, CDCl3)(ppm)：7.10 (d, j=8.6Hz, 2H, Ar-H), 6.90 (d, j=8.6Hz, 2H, Ar-H), 5.10 (s, 2H ,-CH 2), 4.59 (s, 2H ,-CH 2), 3.68 (t, j=7.1Hz, 2H ,-CH 2), 2.84 (t, j= 7.1Hz, 2H ,-CH 2), 2.56 (s, 3H ,-CH 3), 2.50 (s, 6H ,-CH 3), 2.48 (s, 6H ,-CH 3), 2.46 (s, 3H ,-CH 3) .13C-NMR (125MHz, CDCl3)(ppm)：157.2,151.3,150.7,150.1,149.9,148.7,148.4,147.1, 145.9,131.5,129.9,114.8,72.7 (-CH2), 72.0 (-CH2), 70.1 (-CH2), 35.5 (-CH2), 21.8 (-CH3), 21.7(-CH3), 21.5 (-CH3), 21.5 (-CH3), 20.8 (-CH3), 20.5 (-CH3).HRMS(ESI)m/z：[M+H]+calcd for C24H31N4O2：407.24470, found：407.24362.
Embodiment 6
2- ((2-methoxy-4- (((3,5,6-trimethylpyrazin-2-yl) methoxy) methyl) Phenoxy) methyl) -3,5,6-trimeth ylpyrazine (2c)
It takes 308mg (2.0mmol) vanillyl alcohol to be placed in a reaction flask, 20mL N, N- dimethyl formyls is added into reaction bulb After amine stirring and dissolving, 96mg (4.0mmol) NaH is added, after stirring 0.5h, is added dropwise to 682mg (4.0mmol) TMP-Cl in room temperature Continue after being stirred to react 0.5h, the heating reaction 4h in 80 DEG C of oil baths.TLC [V (petroleum ether): V (acetone)=2: 1] detection reactions Substantially completely, stop reaction, cooling, filtering.Filtrate adds the saturated common salt of 5 times of amounts water-dispersed, and 3 are extracted with equivalent ethyl acetate It is secondary, combined ethyl acetate layer, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silicagel column point From white solid 548.68mg.M.P.：108.8-109.0 DEG C, yield 65.0%.
1H-NMR (500MHz, CDCl3)(ppm)：6.98 (d, j=8.1Hz, 1H, Ar-H), 6.90 (s, 1H, Ar-H), 6.84 (d, j=8.1Hz, 1H, Ar-H), 5.18 (s, 2H ,-CH 2), 4.60 (s, 2H ,-CH 2), 4.50 (s, 2H ,-CH 2), 3.83 (s, 3H ,-OCH 3), 2.60 (s, 3H ,-CH 3), 2.52 (s, 3H ,-CH 3), 2.49 (s, 6H ,-CH 3), 2.48 (s, 6H ,-CH 3) .13C-NMR (125MHz, CDCl3)(ppm)：151.2,150.8,150.3,150.0,149.8,148.5,147.8,147.1, 145.9,131.5,120.6,114.3,111.9,72.9,71.6,71.2,56.0,21.8,21.7,21.5,21.5,20.8, 20.7.HRMS(ESI)m/z：[M+H]+calcd for C24H31N4O3：423.23962, found：423.23746.
Embodiment 7
N- (4-hydroxybenzyl) -3,5,6-trimethylpyrazine-2-carboxamide (3a)
246mg (2.0mmol) 4- hydroxy benzylamines, 332mg (2.0mmol) ligustrazine acid, 458mg are sequentially added in round-bottomed bottle (2.4mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, three nitrogen of 324mg (2.4mmol) 1- hydroxy benzos Azoles, 308mg (2.4mmol) n,N-diisopropylethylamine；20mLN, dinethylformamide are added, stirring at normal temperature reacts 12h. TLC [V (petroleum ether): V (acetone)=2: 1] detections reaction substantially completely, stops reaction, filtering.Filtrate adds the saturation food of 5 times of amounts Brine dispersion is extracted 3 times, combined ethyl acetate layer with equivalent ethyl acetate, and with saturated common salt water washing, anhydrous sodium sulfate is dry It is dry, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 506.94mg.M.P.：187.6-188.4 DEG C, yield 93.5%.
1H-NMR (500MHz, DMSO-d6)(ppm)：9.26 (s, 1H, Ar-OH), 8.95 (t, J=5.9Hz, 1H), 7.11 (d, j=8.2Hz, 2H, Ar-H), 6.69 (d, j=8.2Hz, 2H, Ar-H), 4.32 (d, j=6.2Hz, 2H ,-CH 2), 2.65 (s, 3H ,-CH 3), 2.46 (s, 6H ,-CH 3).13C-NMR (125MHz, DMSO-d6)(ppm)：164.9,156.3,153.4, 149.0,147.9,140.5,129.6,128.7,115.0,41.8,21.9,21.5,20.9.HRMS (ESI) m/z：[M+H]+ calcd for C1sH18N3O2：272.13990, found：272.13834.
Embodiment 8
N- (4-hydroxyphenethyl) -3,5,6-trimethylpyrazine-2-carboxamide (3b)
274mg (2.0mmol) tyrasamine, 332mg (2.0mmol) ligustrazine acid, 458mg are sequentially added in round-bottomed bottle (2.4mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, three nitrogen of 324mg (2.4mmol) 1- hydroxy benzos Azoles, 308mg (2.4mmol) n,N-diisopropylethylamine；20mLN, dinethylformamide are added, stirring at normal temperature reacts 12h. TLC [V (petroleum ether): V (acetone)=2: 1] detections reaction substantially completely, stops reaction, filtering.Filtrate adds the saturation food of 5 times of amounts Brine dispersion is extracted 3 times, combined ethyl acetate layer with equivalent ethyl acetate, and with saturated common salt water washing, anhydrous sodium sulfate is dry It is dry, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 502.74mg.M.P.：177.3-177.9 DEG C, yield 88.2%.
1H-NMR (500MHz, DMSO-d6)(ppm)：9.20 (s, 1H, Ar-OH), 8.61 (t, J=5.7Hz, 1H), 7.04 (d, j=8.1Hz, 2H, Ar-H), 6.69 (d, j=8.1Hz, 2H, Ar-H), 3.43 (dd, J=14.2,6.7Hz, 2H ,-CH 2), 2.72 (t, J=7.5Hz, 2H ,-CH 2), 2.65 (s, 3H ,-CH 3), 2.49 (s, 6H ,-CH 3).13C-NMR (125MHz, DMSO- d6)(ppm)：164.9,155.7,153.3,148.9,147.9,140.4,129.5,129.3,115.1,40.6,34.3, 21.9,21.5,20.9.HRMS (ESI) m/z：[M+H]+calcd for C16H20N3O2：286.15555, found： 286.15378.
Embodiment 9
N- (4-hydroxy-3-methoxybenzyl) -3,5,6-trimethylpyrazine-2-carboxamide (3c).
Sequentially added in round-bottomed bottle 378mg (2.0mmol) Vanillylamines hydrochloride, 332mg (2.0mmol) ligustrazine acid, 458mg (2.4mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 324mg (2.4mmol) 1- hydroxy benzenes And triazole, 308mg (2.4mmol) n,N-diisopropylethylamine；Add 20mLN, dinethylformamide, stirring at normal temperature is anti- Answer 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections reaction substantially completely, stops reaction, filtering.Filtrate add 5 times amount Saturated common salt is water-dispersed, is extracted 3 times with equivalent ethyl acetate, combined ethyl acetate layer, with saturated common salt water washing, anhydrous slufuric acid Sodium is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 497.24mg.M.P.：151.3-152.1 DEG C, yield 82.6%.
1H-NMR (500MHz, DMSO-d6)(ppm)：8.94 (s, 1H), 8.83 (s, 1H, Ar-OH), 6.91 (s, 1H, Ar- H), 6.70 (s, 2H, Ar-H), 4.34 (d, j=5.8Hz, 2H ,-CH 2), 3.72 (s, 3H ,-OCH 3), 2.64 (s, 3H ,-CH 3), 2.46 (s, 6H ,-CH 3).13C-NMR (125MHz, DMSO-d6)(ppm)：165.1,153.4,148.9,148.0,147.4, 145.5,140.7,130.2,119.9,115.2,112.0,55.5,42.1,21.9,21.6,21.0.HRMS (ESI) m/z：[M+ H]+calcd for C16H20N3O3：302.15047, found：302.14877.
Embodiment 10
3,5,6-trimethyl-N- (4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) benzyl) pyrazine-2-carboxamide (4a).
271mg (1.0mmol) 3a, 170mg (1.0mmol) TMP-Cl, 138mg (2.0mmol) is sequentially added in round-bottomed bottle Potassium carbonate；Add 20mL n,N-Dimethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (petroleum ether): V (acetone) =2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated aqueous sodium carbonate liquid measured dispersion, uses Equivalent ethyl acetate extracts 3-4 times, combined ethyl acetate layer, is washed to neutral (on a small quantity repeatedly) with saturated sodium-chloride water solution, Anhydrous sodium sulfate is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 349.32mg.M.P.：104.8- 105.7 DEG C, yield 86.3%.
1H-NMR (500MHz, CDCl3)(ppm)：8.27 (s, 1H), 7.28 (d, j=8.3Hz, 2H, Ar-H), 6.98 (d, j =8.3Hz, 2H, Ar-H), 5.14 (s, 2H ,-CH 2), 4.56 (d, j=5.8Hz, 2H ,-CH 2), 2.93 (s, 3H ,-CH 3), 2.58 (s, 3H ,-CH 3), 2.54 (s, 3H ,-CH 3), 2.51 (s, 6H ,-CH 3), 2.48 (s, 3H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：165.0,158.1,154.3,151.6,151.4,150.1,147.7,138.9,131.2,129.3, 115.1,70.1,42.9,23.1,22.1,21.8,21.5,21.5), 20.7.HRMS (ESI) m/z：[M+H]+calcd for C23H28N5O2：406.224302, found：406.22226.
Embodiment 11
3,5,6-trimethyl-N- (4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) phenethyl) pyrazine-2-carboxamide(4b).
285mg (1.0mmol) 3b, 170mg (1.0mmol) TMP-Cl, 138mg (2.0mmol) is sequentially added in round-bottomed bottle Potassium carbonate；Add 20mL n,N-Dimethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (petroleum ether): V (acetone) =2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated aqueous sodium carbonate liquid measured dispersion, uses Equivalent ethyl acetate extracts 3-4 times, combined ethyl acetate layer, is washed to neutral (on a small quantity repeatedly) with saturated sodium-chloride water solution, Anhydrous sodium sulfate is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 326.71mg.M.P.：148.1- 148.9 DEG C, yield 77.9%.
1H-NMR (500MHz, DMSO-d6)(ppm)：8.63 (s, 1H), 7.17 (d, j=7.9Hz, 2H, Ar-H), 6.97 (d, j=7.9Hz, 2H, Ar-H), 5.11 (s, 2H ,-CH 2), 3.46 (d, j=6.4Hz, 2H ,-CH 2), 3.34 (s, 6H ,-CH 3), 2.78 (t, j=7.1Hz, 2H ,-CH2), 2.63 (s, 3H ,-CH 3), 2.48 (s, 3H ,-CH 3), 2.45 (s, 6H ,-CH 3).13C- NMR (125MHz, DMSO-d6)(ppm)：164.9,150.8,149.3,148.9,148.2,147.8,145.5,131.7, 129.6,114.6,69.4,40.5,34.2,21.8,21.5,21.2,20.9,20.1.HRMS (ESI) m/z：[M+H]+calcd for C24H30N5O2：420.23995, found：420.23706.
Embodiment 12
N- (3-methoxy-4- ((3,5,6-trimethylpyrazin-2-yl) methoxy) benzyl) -3,5,6- trimethylpyrazine-2-carboxamide(4c).
301mg (1.0mmol) 3c, 170mg (1.0mmol) TMP-Cl, 138mg (2.0mmol) is sequentially added in round-bottomed bottle Potassium carbonate；Add 20mL n,N-Dimethylformamide, the lower 85 DEG C of reactions 4h of nitrogen protection.TLC [V (petroleum ether): V (acetone) =2: 1] after detection reaction substantially completely, cooling, filtering.Filtrate adds the 5-10 times of saturated aqueous sodium carbonate liquid measured dispersion, uses Equivalent ethyl acetate extracts 3-4 times, combined ethyl acetate layer, is washed to neutral (on a small quantity repeatedly) with saturated sodium-chloride water solution, Anhydrous sodium sulfate is dried, filtering, evaporated under reduced pressure.Residue silica gel post separation obtains white solid 371.38mg.M.P.：134.3- 136.2 DEG C, yield 85.4%.
1H-NMR (500MHz, DMSO-d6)(ppm)：9.04 (t, J=6.1Hz, 1H), 7.04 (d, j=8.2Hz, 1H, Ar- H), 7.00 (s, 1H, Ar-H), 6.84 (d, j=8.0Hz, 1H, Ar-H), 5.09 (s, 2H ,-CH 2), 4.41 (d, j=6.2Hz, 2H ,-CH 2), 3.73 (s, 3H ,-OCH 3), 3.35 (s, 3H ,-CH 3), 2.67 (s, 3H ,-CH 3), 2.50 (s, 6H ,-CH 3), 2.45 (s, 3H ,-CH 3), 2.44 (s, 3H ,-CH 3).13C-NMR (125MHz, DMSO-d6)(ppm)：165.1,153.4,150.9, 149.5,149.2,149.0,148.1,148.0,145.5,140.6,132.8,119.4,114.1,111.9,70.4,55.5, 42.0,21.8,21.5,21.2,20.9,20.9,20.1.HRMS (ESI) m/z：[M+H]+calcd for C24H30N5O3： 436.23486, found：436.23169.
Embodiment 13
4- ((3,5,6-trimethylpyrazine-2-carboxamido) methyl) phenyl 3,5,6- trimethylpyrazine-2-carboxylate(5a).
271mg (1.0mmol) 3a, 166mg (1.0mmol) ligustrazine acid, 229mg are sequentially added in round-bottomed bottle (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL n,N-Dimethylformamide is added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- It should substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 305.29mg.M.P.：148.2-150.0 DEG C, yield 72.9%.
1H-NMR (500MHz, DMSO-d6)(ppm)：9.22 (t, j=6.2Hz, 1H), 7.44 (d, j=8.3Hz, 2H, Ar- H), 7.25 (d, j=8.3Hz, 2H, Ar-H), 4.52 (d, j=6.3Hz, 2H ,-CH 2), 2.70 (s, 6H ,-CH 3), 2.57 (s, 3H ,-CH 3), 2.55 (s, 3H ,-CH 3), 2.51 (s, 6H ,-CH 3).13C-NMR (125MHz, DMSO-d6)(ppm)：165.2 164.1,153.6,149.5,149.3,149.2,148.1,140.2,137.8,137.5,128.6,121.7,41.7,22.2, 22.0,21.9,21.6,21.0,21.0.HRMS (ESI) m/z：[M+H]+calcd for C23H26N5O3：420.20356 found：420.20209.
Embodiment 14
4- (2- (3,5,6-trimethylpyrazine-2-carboxamido) ethyl) phenyl 3,5,6- trimethylpyrazine-2-carboxylate(5b).
285mg (1.0mmol) 3b, 166mg (1.0mmol) ligustrazine acid, 229mg are sequentially added in round-bottomed bottle (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL n,N-Dimethylformamide is added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- It should substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 326.72mg.M.P.：124.7-126.2 DEG C, yield 75.5%.
1H-NMR (500MHz, CDCl3)(ppm)：8.09 (s, 1H), 7.32 (d, J=8.2Hz, 2H, Ar-H), 7.19 (d, J =8.2Hz, 2H, Ar-H), 3.70 (dd, J=13.3,6.7Hz, 2H ,-CH 2), 2.96 (t, J=7.0Hz, 2H ,-CH 2), 2.92 (s, 3H ,-CH 3), 2.82 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.61 (s, 3H ,-CH 3), 2.55 (s, 3H ,-CH 3), 2.49 (s, 3H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：165.2,164.7,155.4,154.2,152.5, 149.7,149.6,139.0,138.6,137.1,130.0,122.0,40.7,35.5,23.0,22.9,22.4,22.1,21.8, 21.5.HRMS(ESI)m/z：[M+H]+calcd for C24H28N5O3：434.21921, found：434.21750.
Embodiment 15
2-methoxy-4- ((3,5,6-trimethylpyrazine-2-carboxamido) methyl) phenyl 3, 5,6-trimethylpyrazine-2-carboxylate (5c)
301mg (1.0mmol) 3c, 166mg (1.0mmol) ligustrazine acid, 229mg are sequentially added in round-bottomed bottle (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL n,N-Dimethylformamide is added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- It should substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 317.63mg.M.P.：167.5-176.9 DEG C, yield 70.7%.
1H-NMR (500MHz, CDCl3)(ppm)：8.33 (s, 1H), 7.17 (d, j=8.0Hz, 2H, Ar-H), 7.02 (s, 1H, Ar-H), 6.99 (d, j=8.1Hz, 2H, Ar-H), 4.64 (d, j=5.8Hz, 2H ,-CH 2), 3.82 (s, 3H ,-OCH 3), 2.94 (s, 3H ,-CH 3), 2.82 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.60 (s, 3H ,-CH 3), 2.56 (s, 3H ,- CH 3), 2.51 (s, 3H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：165.1,164.2,155.2,152.5,151.3, 149.7,139.3,138.8,138.7,137.8,131.0,129.0,123.1,120.3,112.3,56.1,43.3,23.0, 22.9,22.4,22.1,21.8,21.5.HRMS (ESI) m/z：[M+H]+calcd for C24H28N5O4：450.21413 found：450.21216.
Embodiment 16
4- (hydroxymethyl) phenyl 3,5,6-trimethylpyrazine-2-carboxylate (6a)
248mg (2.0mmol) 4- hydroxy-benzyl alcohols, 166mg (1.0mmol) ligustrazine acid, 229mg are sequentially added in round-bottomed bottle (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL anhydrous methylene chlorides are added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detects reactive group This is completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silicagel column point From white solid 98.35mg.M.P.：137.6-138.3 DEG C, yield 46.2%.
1H-NMR (500MHz, CDCl3)(ppm)：7.43 (d, j=8.5Hz, 2H, Ar-H), 7.22 (d, j=8.5Hz, 2H, Ar-H), 4.71 (s, 2H ,-CH 2), 2.82 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.61 (s, 3H ,-CH 3), 2.06 (s, 1H ,-OH)13C-NMR (125MHz, CDCl3)(ppm)：164.6,155.4,152.5,150.3,149.8,139.0,138.5, 128.2,122.0,64.8,22.9,22.4,21.8.HRMS (ESI) m/z：[M+H]+calcd for C15H17N2O3： 273.12392, found：273.12369.
Embodiment 17
4- (2-hydroxyethyl) phenyl 3,5,6-trimethylpyrazine-2-carboxylate (6b)
Sequentially added in round-bottomed bottle 276mg (2.0mmol) p-hydroxyphenylethanol, 166mg (1.0mmol) ligustrazine acid, 229mg (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4- dimethylaminos Pyridine；20mL n,N-Dimethylformamide is added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] Detection reaction is substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.It is residual Slag silica gel post separation obtains white solid 87.62mg.M.P.：153.1-153.7 DEG C, yield 40.7%.
1H-NMR (500MHz, CDCl3)(ppm)：7.29 (d, j=7.6Hz, 2H, Ar-H), 7.19 (d, j=7.6Hz, 2H, Ar-H), 3.87 (t, j=6.4Hz, 2H ,-CH 2), 2.89 (t, j=6.4Hz, 2H ,-CH 2), 2.82 (s, 3H ,-CH 3), 2.63 (s, 6H ,-CH 3), 2.62 (s, 6H ,-CH 3), 1.80 (s, 1H ,-OH)13C-NMR (125MHz, CDCl3)(ppm)：164.7 155.3,152.4,149.8,149.6,138.7,136.7,130.2,122.0,63.7,38.8,22.9,22.4,21.8.HRMS (ESI)m/z：[M+H]+calcd for C16H19N2O3：287.13957, found：287.13821.
Embodiment 18
4- (hydroxymethyl) -2-methoxyphenyl 3,5,6-trimethylpyrazine-2- carboxylate(6c).
308mg (2.0mmol) vanillyl alcohol, 166mg (1.0mmol) ligustrazine acid, 229mg are sequentially added in round-bottomed bottle (1.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL n,N-Dimethylformamide is added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- It should substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 106.25mg.M.P.：142.3-143.4 DEG C, yield 45.3%.
1H-NMR (500MHz, CDCl3)(ppm)：7.16 (d, j=8.0Hz, 2H, Ar-H), 6.95 (d, j=8.0Hz, 2H, Ar-H), 4.70 (s, 2H ,-CH 2), 3.84 (s, 3H ,-OCH 3), 2.83 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.61 (s, 3H ,-CH 3), 2.04 (s, 1H ,-OH)13C-NMR (125MHz, CDCl3)(ppm)：164.1,155.2,152.4,151.3, 149.8,140.4,139.3,138.8,123.0,119.1,111.1,65.1,56.0,22.8,22.4,21.8.HRMS (ESI) m/z：[M+H]+calcd for C16H18N2O4：303.134482, found：303.13190.
Embodiment 19
4- ((3,5,6-trimethylpyrazine-2-carbonyl) oxy) benzyl 3,5,6- trimethylpyrazine-2-carboxylate(7a).
124mg (1.0mmol) 4- hydroxy-benzyl alcohols, 332mg (2.0mmol) ligustrazine acid, 420mg are sequentially added in round-bottomed bottle (2.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL anhydrous methylene chlorides are added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detects reactive group This is completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silicagel column point From white solid 236.42mg.M.P.：83.7-84.6 DEG C, yield 53.5%.
1H-NMR (500MHz, CDCl3)(ppm)：7.56 (d, j=8.2Hz, 2H, Ar-H), 7.27 (d, j=8.2Hz, 2H, Ar-H), 5.46 (s, 2H ,-CH 2), 2.82 (s, 3H ,-CH 3), 2.73 (s, 3H ,-CH 3), 2.63 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.57 (s, 6H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：165.8,164.5,155.5,154.7, 152.6,151.0,149.8,139.5,138.4,133.7,130.0,122.2,66.8,23.0,22.7,22.4,22.3, 21.8,21.7.HRMS (ESI) m/z：[M+Na]+calcd for C23H24N4NaO4：443.16952, found：443.16602.
Embodiment 20
4- (2- ((3,5,6-trimethylpyrazine-2-carbonyl) oxy) ethyl) phenyl 3,5,6- trimethylpyrazine-2-carboxylate(7b).
Sequentially added in round-bottomed bottle 138mg (1.0mmol) p-hydroxyphenylethanol, 332mg (2.0mmol) ligustrazine acid, 420mg (2.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4- dimethylaminos Pyridine；20mL anhydrous methylene chlorides are added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detections are anti- It should substantially completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silica gel Post separation obtains white solid 216.39mg.M.P.：57.6-58.4 DEG C, yield 49.9%.
1H-NMR (500MHz, CDCl3)(ppm)：7.35 (d, j=8.2Hz, 2H, Ar-H), 7.18 (d, j=8.2Hz, 2H, Ar-H), 4.61 (t, j=7.2Hz, 2H ,-CH 2), 3.14 (t, j=7.2Hz, 2H ,-CH 2), 2.81 (s, 3H ,-CH 3), 2.68 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.61 (s, 3H ,-CH 3), 2.57 (brs, 6H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：166.0,164.6,155.4,154.6,152.5,151.3,149.7,149.6,149.3,139.6, 138.6,135.5,130.2,122.0,66.2,34.7,22.9,22.4,22.4,22.3,21.8,21.7.HRMS (ESI) m/z： [M+H]+calcd for C24H27N4O4：435.20323, found：435.20108.
Embodiment 21
2-methoxy-4- (((3,5,6-trimethylpyrazine-2-carbonyl) oxy) methyl) phenyl 3,5,6-trimethylpyrazine-2-carboxylate (7c)
154mg (1.0mmol) vanillyl alcohol, 332mg (2.0mmol) ligustrazine acid, 420mg are sequentially added in round-bottomed bottle (2.2mmol) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 24mg (0.2mmol) 4-dimethylaminopyridine； 20mL anhydrous methylene chlorides are added, stirring at normal temperature reacts 12h.TLC [V (petroleum ether): V (acetone)=2: 1] detects reactive group This is completely.Dichloromethane extracts, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, evaporated under reduced pressure.Residue silicagel column point From white solid 186.54mg.M.P.：101.9-102.8 DEG C, yield 39.5%.
1H-NMR (500MHz, CDCl3)(ppm)：7.20 (d, j=8.1Hz, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 7.10 (d, j=8.1Hz, 1H, Ar-H), 5.43 (s, 2H ,-CH 2), 3.84 (s, 3H ,-CH 3), 2.82 (s, 3H ,-CH 3), 2.73 (s, 3H ,-CH 3), 2.62 (s, 3H ,-CH 3), 2.60 (s, 3H ,-CH 3), 2.57 (s, 6H ,-CH 3).13C-NMR (125MHz, CDCl3)(ppm)：165.8,163.9,155.3,154.8,151.2,149.8,139.9,139.4,138.5,134.9, 123.1,121.1,112.7,67.1,56.0,22.9,22.8,22.5,22.3,21.8,21.8.HRMS (ESI) m/z：[M+Na ]+calcd for C24H26N4NaO5：473.18009, found：473.17734.

Claims (11)

1. ligustrazine replaces p-Hydroxybenzylalcohol analog derivative L QC-F, which is characterized in that the compound includes para hydroxybenzene Methanol analog parent nucleus and the substituent group for including ligustrazine structure, general structure such as formula 1：
Wherein, R1Selected from-OH ,-NH2, 3,5,6- trimethyl ligustrazine -2- methylenes oxygroups, 3,5,6- trimethyl ligustrazine -2- first Acyloxy or 3, any one in 5,6- trimethyl ligustrazine -2- formamidos；R2Selected from-H or-OCH3In any one； R3Selected from-H, 3,5,6- trimethyl ligustrazine -2- methylene or 3,5,6- trimethyl ligustrazine -2- formoxyls any one, And R1-R3In at least one include the substituent group of ligustrazine structure, n is 1 or 2.
2. derivative as described in claim 1, which is characterized in that the p-Hydroxybenzylalcohol analog parent nucleus can be to hydroxyl Any one in base benzyl alcohol, p-hydroxyphenylethanol, vanillyl alcohol, para hydroxybenzene methylamine, Uteramin, Vanillylamine.
3. derivative as described in claim 1, which is characterized in that the derivant structure is 1a, 1b, 1c：
。
4. derivative as described in claim 1, which is characterized in that the derivant structure is 2a, 2b, 2c：
。
5. derivative as described in claim 1, which is characterized in that the derivant structure is 3a, 3b, 3c：
。
6. derivative as described in claim 1, which is characterized in that the derivant structure is 4a, 4b, 4c：
。
7. derivative as described in claim 1, which is characterized in that the derivant structure is 5a, 5b, 5c：
。
8. derivative as described in claim 1, which is characterized in that the derivant structure is 6a, 6b, 6c：
。
9. derivative as described in claim 1, which is characterized in that the derivant structure is 7a, 7b, 7c：
。
10. the derivative as described in claim 1-9 is any is preparing the application in treating brain neuroblastoma damage medicine.
11. application as claimed in claim 10, which is characterized in that the brain neuroblastoma damage disease includes headstroke, old age Any one in dementia, Parkinson's disease, brain trauma.
CN201710089204.0A 2017-02-20 2017-02-20 Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC-F）And its application Pending CN108456178A (en)

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