CN104370738A - Longistyline analogue and application thereof in preparation of antibacterial drug - Google Patents

Longistyline analogue and application thereof in preparation of antibacterial drug Download PDF

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CN104370738A
CN104370738A CN201410570796.4A CN201410570796A CN104370738A CN 104370738 A CN104370738 A CN 104370738A CN 201410570796 A CN201410570796 A CN 201410570796A CN 104370738 A CN104370738 A CN 104370738A
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CN104370738B (en
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陈卫民
叶文才
耿志忠
张建军
林静
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Jinan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings

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Abstract

The invention belongs to the field of medicines and discloses a longistyline analogue and an application thereof in preparation of an antibacterial drug. The longistyline analogue has a structure as shown in the formula I described in the specification, wherein R1 is -H or -CH3, R2 is -H, isopentenyl or geranyl; R3 is -CH3 or described in the specification; R4 is -H, -F, -Cl, -OCH3, -CF3 or -CN, and the substituting number of R4 on a benzene ring is not limited. According to the longistyline analogue and the application thereof in preparation of the antibacterial drug disclosed by the invention, the longistyline is taken as a lead compound to modify and transform C-1-site carboxyl, C-3-site isopentenyl and an aromatic B ring, so that a series of longistyline derivatives, especially fluorine-containing derivatives, are designed and synthesized. The obtained antibacterial drug has relatively good antibacterial activity, especially for drug-resistant bacteria and is found to be better than a positive control drug for methicillin resistant staphylococcus aureus for the first time in such compounds. The obtained antibacterial drug has relatively small toxic and small effect and relatively high safety and can be used in preparation of an antibacterial drug.

Description

Cajanin analog and the application in preparation antibacterials thereof
Technical field
The invention belongs to field of medicaments, particularly a kind of cajanin analog and the application in preparation antibacterials thereof.
Background technology
Superbug is a kind of drug tolerant bacteria, more the appellation of science should be " producing NDM-1 drug-resistant bacteria to draw ", namely NDM-1 gene is carried, can to encode I type New Delhi metallo-β-lactamase, the bacterium no longer responsive to most microbiotic (except Tigecycline, polymyxin).Nearest discovery " producing NDM-1 drug-resistant bacteria " is compared with tradition " superbacteria ", its resistance has been no longer only have " multi-drug resistant " for several microbiotic, but it is all insensitive to most microbiotic, this is called as " general resistance " (pan-drug resistance, PDR) (see external medical microbiotic fascicle, 2011,32 (6), 254-258).Therefore, in the treatment of bacteriological infection in the urgent need to having the novel antibacterial medicine of brand-new skeleton and novel mechanism.
Cajanin be from Leaf of Cajan extraction and isolation to stilbene compound, there is antitumor, hypoglycemic, reducing blood-fat significantly, antiviral, osteoporosis, anti-necrosis of femoral head isoreactivity.Research finds, cajanin has stronger anti-microbial activity to gram-positive microorganisms such as streptococcus aureus, staphylococcus epidermidis, subtilises, MIC value is 13 ~ 25 μ g/mL (see Food Chemistry, 121 (2010), 1150-1155).Good anti-microbial activity is shown equally to methicillin-resistant staphylococcus aureus, bacterium can be killed significantly, be better than the positive control drugs such as penicillin.Cajanin is as natural active compound, and toxicity is less.In order to develop the drug candidate better than cajanin anti-microbial activity, toxic side effect is less, security is higher, the present invention take cajanin as lead compound, modify C-1 position carboxyl, C-3 position isopentene group and fragrant B ring and transform, design and synthesis series wood legumin structurally similar compounds is also tested its antibacterial activity in vitro.
Summary of the invention
In order to overcome the shortcoming of above-mentioned prior art with not enough, primary and foremost purpose of the present invention is to provide a kind of cajanin analog.
Another object of the present invention is to provide the application of described cajanin analog in preparation antibacterials.Cajanin analog anti-microbial activity of the present invention is better, toxic side effect is less, security is higher, particularly has good activity to gram-positive microorganism and resistant organism thereof.Especially to methicillin-resistant staphylococcus aureus, positive control drug is better than.This is be found first time in this compounds.
Object of the present invention is realized by following proposal:
A kind of cajanin analog, has structure shown in formula I:
Wherein, R 1for-H or-CH 3;
R 2for-H, isopentene group or geranyl;
R 3for-CH 3or
R 4for-H ,-F ,-Cl ,-OCH 3,-CF 3or-CN, and do not limit it in the nuclear substituted number of benzene.
Preferably, described cajanin analog has following shown structure:
The synthetic route of cajanin analog of the present invention is as follows:
Synthetic route 1:
As shown in synthetic route 1, particularly, methyl acetoacetate and methyl crotonate in the basic conditions condensation obtain compound 2; Compound 2 replaces through bromine, obtains compound 3; Compound 3, under methylating reagent effect, obtains compound 4; Compound 4 and brominated reagent react, and obtain compound 5; There is Arbuzov and react in compound 5 and triethyl-phosphite, obtains compound 6; Compound 6 sloughs bromine under the effect of palladium, obtains compound 7; Compound 7 and aldehyde are reacted by Witting-honor, obtain A series compound; A series compound is at BCl 3b series compound is obtained Deng demethylation under the effect of halogenation borane reagent; B series compound reacts with haloalkane under NaH effect (or being obtained by Stile linked reaction), obtains R 1for-CH 3c series compound; C series compound is hydrolyzed in the basic conditions, obtains R 1for the cajanin analog of the present invention of-H, i.e. the compound of D series.A compound is directly hydrolyzed in the basic conditions the compound obtaining E series.Add iodine to add in alcohol heat 2, then by the product that obtains and halohydrocarbons reaction, obtain C8, D8.
More specifically, described synthetic method comprises the following steps:
(1) metal Na being dissolved in the alcohols materials such as anhydrous methanol (also can directly use sodium methylate, sodium ethylate to replace), add methyl acetoacetate, heating reflux reaction 0.5 ~ 3h, be cooled to 20 ~ 50 DEG C, drip methyl crotonate, after dropwising, heating reflux reaction 5 ~ 12h, steams methyl alcohol, residuum is added in frozen water, adjust pH is to acid, and extraction, obtains compound 2;
(2) be dissolved in acid by compound 2, under 20 ~ 60 DEG C of conditions, drip the bromine reaction 1h of three times of equivalents, react 18h under normal temperature condition, ice-water bath is separated out, and filters, and collect filter cake, drying obtains compound 3;
(3) compound 3 is dissolved in acetone, adds K 2cO 3, NaCO 3deng carbonate, methyl-sulfate or the methylating reagent such as methylcarbonate or methyl iodide, heating reflux reaction 2 ~ 8h, steams acetone, and residuum joins in NaOH or other basic solutions, extraction.Organic layer washs, dry, and filter, steam solvent, residuum silica gel column chromatography obtains compound 4;
(4) compound 4 is dissolved in the organic solvent such as chloroform, tetracol phenixin, add the radical initiators such as BPO and NBS mixture (also can replace with other brominated reagents) in batches, back flow reaction under illumination condition, filter, collect filtrate, filtrate is washed, dry, filter, steam solvent, obtain compound 5;
(5) be dissolved in alkyl phosphite by compound 5, heating reflux reaction 2 ~ 6h, column chromatography obtains compound 6;
(6) compound 6 is dissolved in organic solvent, adds acid chloride, salt of wormwood or other carbonate, heating reflux reaction 2 ~ 8h, obtain compound 7;
(7) 5-crown ether-5 or other phase-transfer catalysts are joined in anhydrous THF, add NaH, the slow aldehyde dripping compound 7 and be correlated with, react 1 ~ 3h under moving to normal temperature condition after reaction 0.5 ~ 2h, aftertreatment column chromatography obtains compd A;
(8) compd A is dissolved in methylene dichloride, under-20 DEG C of conditions, adds BCl 3reaction 3h, steams methylene dichloride, and residuum extracts, and organic layer washs, dry, and filter, steam solvent, residuum silica gel column chromatography obtains the compounds of this invention B;
(9) compd B is joined in dry toluene or benzene, add the metal hydrides such as NaH, then add halogenated alkane, be warming up to 60 ~ 90 DEG C of reaction 3 ~ 8h.Reaction solution is extracted three times, the water washing of organic layer saturated common salt, column chromatography, obtains R 1for-CH 3the compounds of this invention C;
(10) join in the mixing solutions of alcohol and water by compound 10, add the alkali such as KOH, heating reflux reaction 2 ~ 4h, is cooled to room temperature, adds appropriate acid and reaction solution is adjusted to acidity, separates out white solid, obtains R 1for the compounds of this invention D of-H.
Further, compd B joins in the mixing solutions of alcohol and water by (1), adds the alkali such as KOH, and heating reflux reaction 2 ~ 4h, is cooled to room temperature, adds appropriate acid and reaction solution is adjusted to acidity, separates out white solid, obtains R 1for-H, R 2for-H, R 4be respectively-H ,-OCH 3,-F the compounds of this invention E1, E2, E3.
(2) compound 2 is dissolved in 100mL alcohol, adds a certain amount of I 2, reacting by heating 2 ~ 6h.Obtain colorless solid, by this colorless solid and halohydrocarbon, NaH reacting by heating 2 ~ 6h obtains C8, D8.
The cajanin analog anti-microbial activity of the invention described above is better, toxic side effect is less, security is higher, can be applicable in preparation antibacterials, particularly there is good anti-microbial activity to resistant organism, to methicillin-resistant staphylococcus aureus (MRSA), there is good activity.
Preferably, cajanin analog of the present invention can be applicable to prepare in anti-Staphylococcus aureus medicine.
Described medicine refers to containing at least one in cajanin analog of the present invention or its pharmaceutical salts and solvate.Known, the solvation form of compound and salt do not affect the biologic activity of compound self usually.
Described medicine can contain one or more pharmaceutically acceptable carrier or vehicle.
The present invention, relative to prior art, has following advantage and beneficial effect:
(1) the present invention take cajanin as lead compound, modify C-1 position carboxyl, C-3 position isopentene group and fragrant B ring and transform, a series of cajanin derivative of design and synthesis, especially fluorine-containing cajanin derivative.
(2) gained antifungal activity of the present invention is better, toxic side effect is less, security is higher, and can be applicable to, in preparation antibacterials, particularly has good anti-microbial activity to resistant organism.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
The synthesis (synthesis of compound 7) of embodiment 1:2,4-dimethoxy-6-diethyl phosphite methyl-toluate
Realize through following reactions steps:
(1) synthesis (compound 2) of 2-carbonyl-4-hydroxyl-6-methyl-cyclohexyl-3-alkene methyl carbonate
4.0g (0.175mol) metal Na is dissolved in 250mL anhydrous methanol, adds methyl acetoacetate 18g (0.155mol) under normal temperature condition, reflux 1h.Be cooled to 48 DEG C, slowly drip methyl crotonate 16g (0.160mol) with this understanding, after dropwising, heating reflux reaction 10h.Steam methyl alcohol, residuum is added in 100mL frozen water, and with the hydrochloric acid adjust pH to 2 of 10%, ethyl acetate (100mL × 3) extracts.Organic layer saturated common salt water washing, anhydrous Na 2sO 4drying, filter, steam solvent, residuum petrol ether/ethyl acetate recrystallization obtains white solid 18.2g, and productive rate is 64%. 1H NMR(300MHz,DMSO-D6)：δ11.38(s,1H),5.23(s,1H),3.64(s,3H),3.11(d,J＝10.8Hz,1H),2.44-2.20(m,2H),0.95(d,J＝6.0Hz,3H).ESI-MS(m/z):207.3[M+Na] +.
The synthesis (compound 3) of the bromo-6-methyl-toluate of (2) 2,4-dihydroxyl-3,5-bis-
15g (0.081mol) compound 2 is dissolved in 150mL glacial acetic acid, under 45 DEG C of conditions, drips the glacial acetic acid solution 50mL of bromine 39g (0.243mol), after reacting 1h with this understanding, under being transferred to normal temperature condition, react 18h.Joined by reaction solution in frozen water, have a large amount of white solid to separate out, filter, collect filter cake, dry, residuum obtains white solid 25g through silica gel column chromatography (sherwood oil/acetone), and productive rate is 93%. 1H NMR(300MHz,DMSO-D6)：δ10.38(s,1H),3.83(s,3H),2.30(s,3H). 13C NMR(75MHz,DMSO-D6)：δ168.11,153.52,152.94,135.99,115.59,106.05,99.80,52.94,21.56.ESI-MS(m/z):363.3[M+Na] +.
The synthesis (compound 4) of the bromo-6-methyl-toluate of (3) 2,4-dimethoxy-3,5-bis-
20g (0.059mol) compound 3 is dissolved in 200mL acetone, adds 24.4g (0.177mol) K 2cO 3, methyl-sulfate 22.3g (0.177mol), heating reflux reaction 4h.Steam acetone, residuum joins in the NaOH solution of 50mL 10%, and ethyl acetate (100mL × 3) extracts.Organic layer saturated common salt water washing, anhydrous Na 2sO 4drying, filters, steams solvent, and residuum silica gel column chromatography (petrol ether/ethyl acetate) obtains colorless solid 20.62g, and productive rate is 95%. 1H NMR(300MHz,CDCl 3)：δ3.90(s,1H),3.84(s,1H),3.83(s,1H),2.29(s,3H). 13C NMR(75MHz,CDCl 3)：δ166.75,155.96,154.16,135.95,127.32,116.80,110.93,62.17,60.36,52.61,20.48.ESI-MS(m/z):391.2[M+Na] +.
The synthesis (compound 5) of the bromo-6-bromomethyl-benzoic acid methyl ester of (4) 2,4-dimethoxy-3,5-bis-
18g (0.049mol) compound 4 is dissolved in 200mL tetracol phenixin, add the mixture of 1.0g (0.004mol) BPO and 9.15g (0.051mol) NBS in batches, back flow reaction 6h under 100W illumination condition, filter, collect filtrate, filtrate uses saturated NaHCO successively 3solution, saturated common salt water washing, anhydrous Na 2sO 4drying, filter, steam solvent, residuum silica gel column chromatography obtains colorless solid 17.6g, and productive rate is 80.6%. 1H NMR(300MHz,CDCl 3)：δ4.59(s,2H),3.97(s,3H),3.88(s,3H),3.88(s,3H). 13C NMR(75MHz,CDCl 3)：δ165.89,156.89,155.10,135.17,127.19,116.99,114.75,62.44,60.70,53.02,29.20.ESI-MS(m/z):469.2[M+Na] +.
The synthesis (compound 6) of the bromo-6-diethyl phosphite methyl-toluate of (5) 2,4-dimethoxy-3,5-bis-
15g (33.6mmol) compound 5 is dissolved in 13mL triethyl-phosphite, heating reflux reaction 2h, decompression steams excessive triethyl-phosphite, residuum silica gel column chromatography (sherwood oil/acetone), obtain colourless liquid 14.3g, productive rate is 84%. 1H NMR(300MHz,CDCl 3)：δ3.95(m,4H),3.84(s,3H),3.78(s,6H),3.60(d,J＝22.7Hz,2H),1.17(t,J＝7.1Hz,6H). 13C NMR(75MHz,CDCl 3)：δ166.19,166.17,156.65,156.60,155.53,155.48,131.89,131.76,126.89,126.82,118.01,117.92,113.10,113.03,62.27,62.18,60.43,52.64,32.22,30.38,16.30,16.22.ESI-MS(m/z):505.4[M+H] +.
The synthesis (compound 7) of (6) 2,4-dimethoxy-6-diethyl phosphite methyl-toluates
12g (23.8mmol) compound 6 is dissolved in 150mL propyl carbinol, adds acid chloride 125mg, salt of wormwood 6.5g (47.6mmol), heating reflux reaction 6h.Filter, collect filtrate, decompression steams propyl carbinol, and residuum obtains colourless oil liquid 7g through silica gel column chromatography (sherwood oil/acetone), and productive rate is 85%. 1H NMR(300MHz,CDCl 3)：δ6.52(t,J＝2.4Hz,1H),6.34(t,J＝2.1Hz,1H),4.07-3.91(m,4H),3.84(s,3H),3.78(s,3H),3.76(s,3H),3.28(d,J＝22.3Hz,2H),1.22(t,J＝7.1Hz,6H).ESI-MS(m/z):347.0[M+H] +.
Embodiment 2:(E)-2,4-dimethoxy-6-(2'-fluorostyryl) methyl benzoate (compd A 1)
60mg 15-crown ether-5 is joined in the anhydrous THF of 30mL, add 440mg (11mmol, content 60%) NaH, 0 DEG C is stirred 10min, the THF mixing solutions of slow dropping 3.5g (10mmol) compound 7 and 2-fluorobenzaldehyde 1.24g (10mmol), reacts 3h under moving to normal temperature condition after 30min.Steam THF, residuum joins in 20mL saturated ammonium chloride solution, and methylene dichloride (50mL × 3) extracts, organic layer saturated common salt water washing, anhydrous Na 2sO 4drying, filters, steams solvent, and residuum silica gel column chromatography (petrol ether/ethyl acetate) obtains white solid 2.9g, and productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ7.55(td,J＝7.7,1.7Hz,1H),7.25(dt,J＝4.5,3.9Hz,1H),7.20(d,J＝1.7Hz,2H),7.17-7.02(m,2H),6.80(d,J＝2.1Hz,1H),6.43(d,J＝2.1Hz,1H),3.94(s,3H),3.88(s,3H),3.83(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.44,161.61,158.26,137.45,129.41,129.30,127.71,127.65,127.39,127.34,124.82,124.66,124.30,124.25,123.99,123.94,116.02,115.96,115.67,101.53,98.31,56.00,55.51,52.36.ESI-MS(m/z):317.1[M+H] +.
Embodiment 3:(E) synthesis (compound B-11) of-2-hydroxyl-4-methoxyl group-6-(2'-fluorostyryl) methyl benzoate
2g (6.3mmol) compd A 1 is dissolved in 50mL methylene dichloride, under-20 DEG C of conditions, adds the BCl of 10mL 3dichloromethane solution (1mol/L), and react 2h with this understanding.Steam solvent, residuum joins saturated NaHCO 3in, methylene dichloride (50mL × 3) extracts, the water washing of organic layer saturated common salt, anhydrous Na 2sO 4drying, filters, steams solvent, and residuum silica gel column chromatography (petrol ether/ethyl acetate) obtains white solid 1.71g, and productive rate is 90%. 1H NMR(300MHz,CDCl 3)：δ11.72(s,1H),7.80(d,J＝16.1Hz,1H),7.57(td,J＝7.6,1.7Hz,1H),7.32-7.22(m,1H),7.13(m,2H),6.95(d,J＝16.1Hz,1H),6.66(d,J＝2.6Hz,1H),6.47(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.60,165.15,164.19,142.79,132.43,132.36,129.07,128.96,127.64,127.59,125.30,125.14,124.29,124.24,123.34,123.30,116.07,115.78,108.14,103.98,100.38,55.52,52.25.ESI-MS(m/z):303.5[M+H] +.
Embodiment 4:(E) synthesis (Compound C 1) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(2'-fluorostyryl) methyl benzoate
1.51g (5mmol) compound B-11 is joined in 50mL dry toluene, adds 240mg (6mmol, content 60%) NaH and isoprenyl bromide 0.89g (6mmol), be warming up to 78 DEG C of reaction 4h.Reaction solution is joined the saturated NaHCO of 20mL 3in, ether (50mL × 3) extracts, organic layer saturated common salt water washing, anhydrous Na 2sO 4drying, filters, steams solvent, and residuum obtains white solid 0.81g through silica gel column chromatography (cyclohexane/ethyl acetate), and productive rate is 44%. 1H NMR(300MHz,CDCl 3)：δ7.80(d,J＝16.2Hz,1H),7.57(td,J＝7.6,1.6Hz,1H),7.25(m,1H),7.20-7.04(m,2H),6.92(d,J＝16.1Hz,1H),6.62(s,1H),5.29-5.13(m,1H),3.94(s,3H),3.93(s,3H),3.39(d,J＝7.0Hz,2H),1.80(s,3H),1.69(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.89,162.12,161.46,161.38,140.23,133.13,133.06,131.94,128.96,128.85,127.45,127.40,125.42,125.26,124.31,124.26,122.41,122.04,116.89,116.05,115.76,104.54,102.94,55.70,52.24,25.87,22.16,17.84.ESI-MS(m/z):371.2[M+H] +；HRMS(ESI):Calcd for[M+H] +C 22H 24FO 4,371.16531；found,371.16547.
Embodiment 5:(E)-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(2'-fluorostyryl) benzoic synthesis (Compound D 1)
0.37g (1mmol) Compound C 1 is joined in the mixing solutions of ethanol 15mL and water 6mL, adds 168mg (3mmol) KOH, heating reflux reaction 2h.Be cooled to room temperature, the hydrochloric acid with 10% adjusts pH to 2, separates out a large amount of white solid, filters, and collects filter cake, and gained crude on silica gel column chromatography (sherwood oil/acetone) obtains white solid 329mg, and productive rate is 92.5%. 1H NMR(300MHz,Acetone-d6):δ8.10(d,J＝16.2Hz,1H),7.73(td,J＝7.7,1.7Hz,1H),7.40-7.30(m,1H),7.28-7.13(m,2H),7.08(d,J＝16.2Hz,1H),6.86(s,1H),5.38-5.07(m,1H),4.01(s,3H),3.37(d,J＝7.2Hz,2H),1.78(s,3H),1.65(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.24,162.08,161.55,140.73,133.13,133.07,130.74,129.28,129.16,127.66,127.62,125.44,125.28,124.58,124.53,122.25,122.16,122.12,116.28,115.79,115.49,104.05,102.70,55.34,25.02,21.80,17.00.ESI-MS(m/z):357.3[M+H] +.HRMS(ESI):Calcd for[M+H] +C 21H 22FO 4,357.14966；found,357.14944.
Embodiment 6:(E)-2,4-dimethoxy-6-(3'-fluorostyryl) methyl benzoate (compd A 2)
With compound 7 for raw material, preparation method is with embodiment 7, and the mol ratio of raw material dosage is identical with embodiment 7, obtains white solid A2, and productive rate is 88%. 1H NMR(300MHz,CDCl 3)：δ7.30(td,J＝7.9,5.9Hz,1H),7.22(d,J＝7.8Hz,1H),7.19-7.13(m,1H),7.12-6.91(m,3H),6.74(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.92(s,3H),3.87(s,3H),3.82(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.38,158.33,139.25,139.15,137.13,130.56,130.52,130.21,130.09,126.80,122.72,122.68,116.00,115.02,114.74,113.27,112.98,101.63,98.33,56.04,55.52,52.43.ESI-MS(m/z):317.2[M+H] +.
Embodiment 7:(E) synthesis (compd B 2) of-2-hydroxyl-4-methoxyl group-6-(3'-fluorostyryl) methyl benzoate
With compd A 2 for raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid, and productive rate is 90%. 1H NMR(300MHz,CDCl 3)：δ11.72(s,1H),7.80(d,J＝16.1Hz,1H),7.57(td,J＝7.6,1.7Hz,1H),7.32-7.22(m,1H),7.16-7.25(m,2H),6.95(d,J＝16.1Hz,1H),6.66(d,J＝2.6Hz,1H),6.47(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.53,165.22,164.17,142.30,139.82,139.72,131.21,130.26,130.14,129.61,129.58,122.68,122.65,114.76,114.48,113.03,112.74,108.16,103.92,100.40,55.50,52.36.ESI-MS(m/z):303.5[M+Na] +.
Embodiment 8:(E) synthesis (Compound C 2) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(3'-fluorostyryl) methyl benzoate
With compd B 2 for raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid C2, and productive rate is 40%. 1H NMR(300MHz,CDCl 3)：δ11.72(s,1H),7.74(d,J＝15.9Hz,1H),7.44-7.15(m,3H),7.06-6.92(m,1H),6.75(d,J＝15.9Hz,1H),6.61(s,1H),3.96(s,3H),3.95(s,3H),3.41(d,J＝7.1Hz,2H),1.82(s,3H),1.71(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.82,161.52,161.36,139.95,139.85,139.79,132.03,131.99,130.25,130.14,128.84,122.56,122.53,121.98,116.99,114.65,114.36,113.01,112.72,104.53,102.92,55.69,52.36,25.86,22.16,17.84.ESI-MS(m/z):371.4[M+H] +；HRMS(ESI):Calcd for[M+H] +C 22H 24FO 4,371.16531；found,371.16427.
Embodiment 9:(E)-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(3'-fluorostyryl) benzoic synthesis (Compound D 2)
With Compound C 2 for raw material, preparation method is with embodiment 10, and raw material dosage mol ratio is identical with embodiment 10, obtains white solid D2, and productive rate is 94%. 1H NMR(300MHz,Acetone-d6)：δ8.08(d,J＝16.1Hz,1H),7.54-7.26(m,3H),7.16-6.95(m,2H),6.88(s,1H),5.30-5.13(m,1H),3.99(s,3H),3.36(d,J＝7.3Hz,2H),1.78(s,3H),1.65(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.21,162.02,161.46,140.55,140.42,131.93,130.72,130.51,130.40,128.88,122.80,122.77,122.26,116.22,114.25,113.97,112.82,112.53,104.20,102.60,55.32,25.01,21.80,16.99.ESI-MS(m/z):357.3[M+H] +；HRMS(ESI):Calcd for[M+H] +C 21H 22FO 4,357.14966；found,357.14994.
Embodiment 10:(E)-2,4-dimethoxy-6-(4'-chloro-styrene base) methyl benzoate (compound A-13)
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains obtaining white solid 3.09g, and productive rate is 93%. 1H NMR(300MHz,CDCl 3)：δ7.44-7.36(m,1H),7.35-7.28(m,1H),7.07(d,J＝16.1Hz,1H),6.97(d,J＝16.1Hz,1H),6.74(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.92(s,1H),3.87(s,1H),3.83(s,1H). 13CNMR(75MHz,CDCl 3)：δ168.43,161.60,158.34,137.27,135.39,133.69,130.44,128.87,127.96,126.06,115.94,101.60,98.22,56.04,55.50,52.38.ESI-MS(m/z):333.3[M+H] +.
Embodiment 11:(E)-2-hydroxyl-4-methoxyl group-6-(4'-chloro-styrene base) methyl benzoate (compd B 3)
Take compound A-13 as raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid 1.64g, and productive rate is 86%. 1H NMR(300MHz,CDCl 3)：δ11.66(s,1H),7.65(d,J＝16.0Hz,1H),7.46-7.38(m,2H),7.37-7.29(m,2H),6.74(d,J＝15.9Hz,1H),6.60(d,J＝2.6Hz,1H),6.44(d,J＝2.6Hz,1H),3.94(s,3H),3.84(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.53,165.18,164.18,142.47,135.92,133.43,130.49,129.54,128.91,127.81,108.07,103.93,100.34,55.51,52.31.ESI-MS(m/z):319.3[M+H] +.
Embodiment 12:(E) synthesis (Compound C 3) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(4'-chloro-styrene base) methyl benzoate
With compound 2-3 for raw material, preparation method is with embodiment 2, and raw material dosage mol ratio is identical with embodiment 2, and obtaining white solid C3 productive rate is 43.4%. 1H NMR(300MHz,CDCl 3)：δ11.68(s,1H),7.68(d,J＝15.9Hz,1H),7.43(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.72(d,J＝15.9Hz,1H),6.58(s,1H),5.22(t,J＝7.0Hz,1H),3.38(d,J＝7.0Hz,2H),1.80(s,3H),1.69(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.83,161.49,161.35,139.94,136.04,133.30,131.97,131.31,128.92,128.77,127.75,121.99,116.89,104.51,102.85,55.68,52.32,25.86,22.16,17.84.ESI-MS(m/z):409.3[M+Na] +.
Embodiment 13:(E)-6-(4'-chloro-styrene base) the benzoic synthesis (compound d3) of-2-hydroxyl-3-isopentene group-4-methoxyl group
With Compound C 3 for raw material, preparation method is with embodiment 3, and raw material dosage mol ratio is identical with embodiment 3, obtains white solid D3 productive rate 92%. 1H NMR(300MHz,Acetone-d6)：δ12.29(s,1H),8.01(d,J＝16.1Hz,1H),7.59(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),7.01(d,J＝16.0Hz,1H),6.86(s,1H),5.22(t,J＝7.1Hz,1H),3.98(s,3H),3.36(d,J＝7.1Hz,2H),1.78(s,3H),1.65(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.23,162.10,161.53,140.60,136.68,132.65,131.18,130.72,128.89,128.72,128.13,122.28,116.17,103.94,102.61,55.31,25.03,21.81,17.01.ESI-MS(m/z):395.3[M+Na] +；HRMS(ESI):Calcd for[M+H] +C 21H 22ClO 4,373.12011；found,373.11735.
Embodiment 14:(E)-2,4-dimethoxy-6-(3'-cyano-styrene base) methyl benzoate (compd A 4)
With compound 7 for raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid 3.23g, and productive rate is 87%. 1H NMR(300MHz,CDCl 3)：δ7.69(dd,J＝7.4,6.2Hz,2H),7.54(dt,J＝7.6,1.3Hz,1H),7.45(t,J＝7.7Hz,1H),7.15(d,J＝16.2Hz,1H),6.98(d,J＝16.1Hz,1H),6.73(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),3.93(s,3H),3.88(s,3H),3.83(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.25,161.69,158.48,138.14,136.77,131.18,130.70,130.26,129.52,129.29,128.21,118.44,116.10,112.96,101.83,98.66,56.09,55.55,52.48.ESI-MS(m/z):324.3[M+H] +.
Embodiment 15:(E) synthesis (compd B 4) of-2-hydroxyl-4-methoxyl group-6-(3'-cyano-styrene base) methyl benzoate
With compd A 4 for raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid B4, and productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ11.64(s,1H),7.80-7.63(m,3H),7.54(dt,J＝7.6,1.3Hz,1H),7.47(d,J＝7.7Hz,1H),6.73(d,J＝16.0Hz,1H),6.58(d,J＝2.4Hz,1H),6.45(d,J＝2.6Hz,1H),3.94(s,3H),3.84(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.30,165.24,164.21,141.81,138.66,132.54,130.93,130.76,129.95,129.57,128.37,118.77,112.98,108.36,103.91,100.66,55.55,52.44.ESI-MS(m/z):310.3[M+H] +.
Embodiment 16:(E) synthesis (Compound C 4) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(3'-cyano-styrene base) methyl benzoate
With compd B 4 for raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid C4, and productive rate is 36%. 1H NMR(300MHz,CDCl 3)：δ11.66(s,1H),7.72(d,J＝16.0Hz,1H),7.60(m,2H),7.55(dd,J＝6.4,1.3Hz,1H),7.48(t,J＝7.7Hz,1H),6.73(d,J＝16.0Hz,1H),6.57(s,1H),5.27-5.15(m,1H),3.94(s,3H),3.93(s,3H),3.38(d,J＝7.1Hz,2H),1.79(s,3H),1.68(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.60,161.54,161.38,139.29,138.78,133.35,132.09,130.85,130.62,129.99,129.57,127.65,121.84,118.81,117.39,112.98,104.55,103.01,55.72,52.46,25.86,22.18,17.84.ESI-MS(m/z):378.0[M+H] +.HRMS(ESI):Calcd for[M+H] +C 23H 24NO 4,378.16998；found,378.16907.
Embodiment 17:(E)-6-(3'-cyano-styrene base) the benzoic synthesis (Compound D 4) of-2-hydroxyl-3-isopentene group-4-methoxyl group
With Compound C 4 for raw material, preparation method is with embodiment 10, and raw material dosage mol ratio is identical with embodiment 10, obtains white solid D4, productive rate 88%. 1H NMR(300MHz,Acetone-d6)：δ8.16(d,J＝16.1Hz,1H),8.05-7.85(m,3H),7.65(m,2H),7.06(d,J＝16.1Hz,1H),6.88(s,1H),5.22(m,1H),3.99(s,3H),3.36(d,J＝7.2Hz,3H),1.78(s,3H),1.65(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.19,162.03,161.45,140.16,139.22,133.01,130.79,130.72,129.95,129.85,127.91,122.22,118.39,116.45,112.77,104.27,102.72,55.34,,25.02,21.82,17.00.ESI-MS(m/z):364.3[M+H] +.HRMS(ESI):Calcd for[M+H] +C 22H 22NO 4,364.15433；found,364.15387.
Embodiment 18:(E)-2,4-dimethoxy-6-(4'-trifluoromethyl styrene base) methyl benzoate (compound A-45)
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains white solid 3.87g, and productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ7.56(q,J＝8.6Hz,4H),7.18(d,J＝16.1Hz,1H),7.03(d,J＝16.1Hz,1H),6.75(d,J＝2.1Hz,1H),6.43(d,J＝2.1Hz,1H),3.93(s,3H),3.86(s,3H),3.82(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.33,161.66,158.41,140.35,136.96,130.16,128.02,126.89,125.69,125.64,125.59,125.54,116.10,101.77,98.50,56.02,55.48,52.38.ESI-MS(m/z):367.1[M+H] +.
Embodiment 19:(E) synthesis (compd B 5) of synthesis of-2-hydroxyl-4-methoxyl group-6-(4'-trifluoromethyl styrene base) methyl benzoate
Take compound A-45 as raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid B5, and productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ11.71(s,1H),7.63(d,J＝15.9Hz,1H),7.47(m,1H),7.08(t,J＝8.7Hz,2H),6.78(d,J＝15.9Hz,1H),6.63(d,J＝2.4Hz,1H),6.46(d,J＝2.6Hz,1H),3.97(s,3H),3.87(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.61,165.18,164.17,160.82,142.67,133.56,129.66,128.22,128.11,115.86,115.57,108.02,103.92,100.21,55.51,52.33.
Embodiment 20:(E) synthesis (Compound C 5) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(4'-trifluoromethyl styrene base) methyl benzoate
With compd B 5 for raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid C5, and productive rate is 34%. 1H NMR(300MHz,CDCl 3)：δ11.67(s,1H),7.80(d,J＝15.9Hz,1H),7.67-7.55(m,4H),6.78(d,J＝16.0Hz,1H),6.60(s,1H),5.22(m,1H),3.93(s,6H),3.39(d,J＝7.1Hz,2H),1.80(s,3H),1.69(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.71,161.54,161.38,139.58,133.23,132.03,128.51,126.66,125.72,125.67,121.91,117.25,104.57,102.98,55.70,52.34,25.85,22.18,17.83ESI-MS(m/z):421.4[M+H] +.HRMS(ESI):Calcd for[M+H] +C 23H 24F 3O 4,421.16212；found,421.16102.
Embodiment 21:(E)-6-(4'-trifluoromethyl styrene base) the benzoic synthesis (Compound D 5) of-2-hydroxyl-3-isopentene group-4-methoxyl group
With Compound C 5 for raw material, preparation method is with embodiment 10, and raw material dosage mol ratio is identical with embodiment 10, obtains white solid D5, productive rate 93%. 1H NMR(300MHz,CDCl 3)：δ11.51(s,1H),7.92(d,J＝16.0Hz,1H),7.74-7.56(m,4H),6.83(d,J＝15.9Hz,1H),6.64(s,1H),5.20(t,J＝7.1Hz,1H),3.96(s,3H),3.38(d,J＝7.1Hz,2H),1.79(s,3H),1.69(s,3H). 13C NMR(75MHz,CDCl 3)：δ175.04,162.53,162.31,141.05,132.94,132.14,129.21,126.88,125.66,121.72,117.37,103.46,103.03,55.79,25.83,22.13,17.81.ESI-MS(m/z):429.3[M+Na] +.HRMS(ESI):Calcd for[M+H] +C 22H 22F 3O 4,407.14647；found,407.14422.
Embodiment 22:(E)-2,4-dimethoxy-6-(4'-trifluoromethyl styrene base) methyl benzoate (compd A 6)
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains white solid 3.87g, and productive rate is 92%.1H NMR(300MHz,CDCl3)δ7.56–7.43(m,1H),7.10(s,2H),6.92–6.77(m,2H),6.75(d,J＝2.0Hz,1H),6.42(d,J＝2.0Hz,1H),3.92(s,1H),3.87(s,1H),3.82(s,1H).13C NMR(75MHz,CDCl3)δ168.40,164.16,164.04,162.23,162.07,161.63,158.68,158.31,137.36,128.20,127.32,123.01,121.31,121.26,121.15,121.09,115.98,111.86,111.81,111.57,111.53,104.51,104.17,103.83,101.51,98.34,56.04,55.54,52.38.ESI-MS(m/z):335.3[M+H] +.
Embodiment 23:(E) synthesis (compound B-26) of-2-hydroxyl-4-methoxyl group-6-(2', 4'-difluorobenzene vinyl) methyl benzoate
With compd A 6 for raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid B6, and productive rate is 95%. 1H NMR(300MHz,CDCl3)δ11.70(s,1H)，7.72(d,J＝16.1Hz,1H),7.53(td,J＝8.6,6.5Hz,1H),6.97(d,J＝16.1Hz,1H),6.96–6.77(m,2H),6.63(d,J＝2.5Hz,1H),6.47(d,J＝2.6Hz,1H),3.96(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)δ171.52,165.17,164.20,142.60,132.07,132.03,128.52,128.45,128.40,128.32,122.40,121.74,121.69,121.56,121.55,111.82,111.78,111.54,111.49,108.16,104.60,104.26,103.93,100.39,55.53,52.26.ESI-MS(m/z):321.1[M+H] +.
Embodiment 24:(E) synthesis (Compound C 6) of-2-hydroxyl-3-isopentene group-4-methoxyl group-6-(2', 4'-difluorobenzene vinyl) methyl benzoate
Take compound B-26 as raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid C6, and productive rate is 34%.1H NMR(300MHz,CDCl3)δ11.67(s,1H),7.72(d,J＝16.1Hz,1H),7.56-7.49(m,1H),6.98–6.8(m,2H),6.83(d,J＝16.1Hz,1H),6.59(s,1H),5.24-5.20(m,1H),3.93(s,6H),3.38(d,J＝7.1Hz,2H),1.80(s,3H),1.68(s,3H).13C NMR(75MHz,CDCl3)δ171.80,161.47,161.38,140.05,132.75,131.97,128.27,128.14,121.99,121.51,118.16,111.83,111.47,104.56,104.51,104.23,103.88,102.89,55.69,52.25,25.86,22.16,17.83.ESI-MS(m/z):461.2[M+H] +.
Embodiment 25:(E)-6-(2', 4'-difluorobenzene vinyl) the benzoic synthesis (Compound D 6) of-2-hydroxyl-3-isopentene group-4-methoxyl group
With Compound C 6 for raw material, preparation method is with embodiment 10, and raw material dosage mol ratio is identical with embodiment 10, obtains white solid D6, and productive rate is 34%.1H NMR(300MHz,Acetone)δ8.05(d,J＝16.2Hz,1H),7.85–7.71(m,1H),7.13–7.06(m,2H),7.02(d,J＝16.1Hz,1H),6.85(s,1H),5.41–5.08(m,1H),4.00(s,3H),3.36(d,J＝7.2Hz,2H),1.78(s,3H),1.65(s,3H).13C NMR(75MHz,Acetone)δ173.19,163.59,162.08,161.56,158.30,140.61,132.98,130.76,128.88,122.22,121.98,121.23,116.31,111.88,111.79,111.64,111.59,104.23,104.00,103.89,103.54,102.71,55.34,25.02,21.80,16.99.
Embodiment 26:(E)-2,4-dimethoxy-6-(4'-fluorostyryl) methyl benzoate (compd A 7)
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains white solid 2.8g, and productive rate is 89%. 1H NMR(300MHz,CDCl 3)：δ7.52-7.34(m,2H),7.13-6.83(m,4H),6.74(d,J＝2.1Hz,1H),6.40(d,J＝2.1Hz,1H),3.93(s,3H),3.83(s,3H),3.79(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.48,161.58,158.29,137.36,133.13,133.08,130.49,128.41,128.30,125.16,125.13,115.87,115.75,115.46,101.53,97.97,55.89,55.37,52.26.ESI-MS(m/z):317.1[M+H] +.
Embodiment 27:(E)-2-hydroxyl-4-methoxyl group-6-(4'-fluorostyryl) methyl benzoate (compd B 7)
With compd A 7 for raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid 1.75g, and productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ11.67(s,1H),7.60(d,J＝15.9Hz,1H),7.51-7.39(m,2H),7.06(t,J＝8.7Hz,2H),6.76(d,J＝15.9Hz,1H),6.60(d,J＝2.6Hz,1H),6.44(d,J＝2.6Hz,1H),3.94(s,3H),3.85(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.58,165.18,164.18,142.67,133.57,129.65,128.21,128.10,115.84,115.55,107.99,103.94,100.23,55.49,52.29.ESI-MS(m/z):303.2[M+H] +.
Embodiment 28:(E) synthesis (Compound C 7) of-2-hydroxyl-3-geranyl-4-methoxyl group-6-(4'-fluorostyryl) methyl benzoate
With compd B 7 for raw material, preparation method is with embodiment 9, and raw material dosage mol ratio is identical with embodiment 9, obtains white solid C7, and productive rate is 38%. 1H NMR(300MHz,CDCl 3)：δ11.68(s,1H),7.63(d,J＝15.9Hz,1H),7.54-7.40(m,2H),7.07(t,J＝8.7Hz,2H),6.74(d,J＝16.0Hz,1H),6.59(s,1H),5.22(dd,J＝7.1,6.0Hz,1H),5.07(dd,J＝9.5,3.9Hz,3H),3.94(s,3H),3.92(s,3H),3.39(d,J＝7.0Hz,2H),1.79(s,3H),1.65(s,3H),1.58(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.90,161.52,161.41,140.10,135.38,133.74,131.20,130.49,130.46,128.84,128.13,128.02,124.47,121.87,116.82,115.85,115.56,104.48,102.80,55.65,52.30,39.84,26.75,25.71,22.09,17.69,16.16.ESI-MS(m/z):439.2[M+H] +.HRMS(ESI):Calcd for[M+H] +C 27H 32FO 4,439.22791；found,439.22682.
Embodiment 29:(E)-2-hydroxyl-3-geranyl-4-methoxyl group-6-(4'-fluorostyryl) benzoic synthesis (Compound D 7)
With Compound C 7 for raw material, preparation method is with embodiment 10, and raw material dosage mol ratio is identical with embodiment 10, prepares Compound D 7 (95%). 1H NMR(300MHz,Acetone-d6)：δ7.96(d,J＝16.0Hz,1H),7.62(dd,J＝8.7,5.5Hz,2H),7.16(t,J＝8.8Hz,2H),7.01(d,J＝16.0Hz,1H),6.86(s,1H),5.24(dd,J＝7.2,6.2Hz,1H),5.08(t,J＝6.8Hz,1H),3.99(s,3H),3.38(d,J＝7.2Hz,3H),1.79(s,3H),1.62(s,3H),1.56(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.33,163.91,163.10,162.13,161.67,161.55,160.75,160.66,140.80,134.38,134.32,130.69,130.29,129.02,128.47,128.36,124.26,122.26,116.06,115.57,115.28,103.95,102.53,55.31,39.64,26.51,24.95,21.74,16.82,15.34.ESI-MS(m/z):425.3[M+H] +.HRMS(ESI):Calcd for[M+H] +C 26H 30FO 4,425.21226；found,425.21404.
Embodiment 30:2-hydroxyl-4-methoxyl group-6-methyl-toluate (compound 3')
5g (27mmol) compound 2 is dissolved in 100mL methyl alcohol, adds 13.8g (54mmol) I 2, heating reflux reaction 4h.Steam excessive methanol, residuum joins the saturated Na of 100mL 2s 2o 3in, ethyl acetate (100mL × 3) extracts.Organic layer saturated common salt water washing, anhydrous Na 2sO 4drying, filter, steam solvent, residuum silica gel column chromatography (petrol ether/ethyl acetate), obtains colorless solid 2.85g, and productive rate is 54%. 1H NMR(300MHz,CDCl 3)：δ11.77(s,1H),6.30(d,J＝2.6Hz,1H),6.25(d,J＝2.6Hz,1H),3.90(s,3H),3.77(s,3H),2.46(s,3H). 13CNMR(75MHz,CDCl 3)：δ172.19,165.54,163.91,143.09,111.09,105.18,98.66,55.22,51.77,24.30.
The synthesis (Compound C 8) of embodiment 31:2-hydroxyl-3-isopentene group-4-methoxyl group-6-methyl-toluate
400mg (2mmol) compound 3' is dissolved in 50mL dry toluene, adds 80mg NaH and isoprenyl bromide 500mg (2.3mmol), be warming up to 78 DEG C of reaction 6h.Reaction solution is joined the saturated NaHCO of 20mL 3in solution, ether (50mL × 3) extracts, saturated common salt water washing, anhydrous Na 2sO 4drying, filters, steams solvent, and residuum silica gel column chromatography (cyclohexane/ethyl acetate) obtains white solid 227mg, and productive rate is 43%. 1H NMR(300MHz,CDCl 3)：δ11.80(s,1H),6.28(s,1H),5.43-4.90(m,1H),3.92(s,3H),3.85(s,3H),3.33(d,J＝7.0Hz,2H),2.52(s,3H),1.78(s,3H),1.67(s,3H). 13C NMR(75MHz,CDCl 3)：δ172.51,161.87,161.09,140.59,131.58,122.46,114.71,106.12,105.69,55.48,51.81,25.84,24.71,21.92,17.80.ESI-MS(m/z):265.3[M+H] +.
The synthesis (Compound D 8) of embodiment 32:2-hydroxyl-3-isopentene group-4-methoxyl group-6 tolyl acid
200mg (0.76mmol) Compound C 8 is joined in the mixed solvent of ethanol 10mL and water 4mL, adds 127mg (2.28mmol) KOH, heating reflux reaction 2h.Be cooled to room temperature, the hydrochloric acid dripping 10% adjusts pH to 2, separates out a large amount of white solid, filters, and collect filter cake, crude product obtains white solid 127mg through petrol ether/ethyl acetate recrystallization, and productive rate is 92%. 1H NMR(300MHz,Acetone-d6)：δ6.49(s,1H),5.33-5.07(m,1H),3.90(s,3H),3.30(d,J＝7.2Hz,2H),2.59(s,3H),1.75(s,3H),1.63(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.80,162.52,161.31,141.30,130.30,122.68,114.03,106.07,105.07,55.10,24.99,23.75,21.56,16.94.ESI-MS(m/z):251.3[M+H] +；HRMS(ESI):Calcd for[M+H] +C 14H 19O 4,251.12779；found,251.12711.
Embodiment 33:(E) synthesis (compd A 9) of-2,4-dimethoxy-6-(styryl) methyl benzoate
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains white solid, and productive rate is 90%. 1H NMR(300MHz,CDCl 3):δ7.49(d,J＝7.2Hz,2H),7.40-7.24(m,3H),7.14(d,J＝16.1Hz,1H),7.06(d,J＝16.1Hz,1H),6.79(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),3.94(s,3H),3.86(s,3H),3.82(s,3H). 13C NMR(75MHz,CDCl 3):δ168.52,161.59,158.29,137.56,136.89,131.78,128.74,128.13,126.82,125.43,115.97,101.57,98.05,56.00,55.49,52.35.ESI-MS(m/z):299.3[M+H] +.
Embodiment 34:(E) synthesis (compd B 9) of-2-hydroxyl-4-methoxyl group-6-(styryl) methyl benzoate
With compd A 2 for raw material, preparation method is with embodiment 1, and raw material dosage mol ratio is identical with embodiment 1, obtains white solid 3.6g, and productive rate is 95%. 1H NMR(300MHz,CDCl 3)：δ11.70(s,1H),7.70(d,J＝16.0Hz,1H),7.54-7.46(m,2H),7.43-7.34(m,2H),7.31(m,1H),6.81(d,J＝15.9Hz,1H),6.64(d,J＝2.6,1H),6.45(d,J＝2.6Hz,1H),3.95(s,3H),3.85(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.69,165.16,164.17,142.88,137.41,130.87,129.86,128.77,127.85,126.68,108.01,103.98,100.21,55.50,52.30.ESI-MS(m/z):591.5[2M+Na] +.
Embodiment 35:(E)-2-hydroxyl-4-methoxyl group-6-(styryl) benzoic synthesis (compd E 1)
285mg (1mmol) (E)-2-hydroxyl-4-methoxyl group-6-(styryl) methyl benzoate is dissolved in the mixed solvent of ethanol 15mL and water 5mL, add 170mg (3mmol) KOH, heating reflux reaction 2h.Be cooled to room temperature, the hydrochloric acid with 10% adjusts pH to 2, separates out a large amount of white solid, filters, and collects filter cake, and crude on silica gel column chromatography (sherwood oil/acetone) obtains white solid 238mg, and productive rate is 88%. 1H NMR(300MHz,Acetone-d6)：δ7.88(d,J＝16.0Hz,1H),7.54-7.48(m,2H),7.23-7.38(m,2H),7.30-7.22(m,1H),6.87(d,J＝16.0Hz,1H),6.68(d,J＝2.4Hz,1H),6.42(d,J＝2.5Hz,1H),3.86(s,3H). 13C NMR(75MHz,Acetone-d6)：δ173.01,164.90,164.04,143.04,137.60,130.32,129.52,128.28,127.34,126.33,106.30,104.32,99.77,54.56.HRMS(ESI):Calcd for[M+H] +C 16H 15O 4,271.09649；found,271.09309.
Embodiment 36:(E)-2,4-dimethoxy-6-(4'-methoxy styryl) methyl benzoate (compd A 10)
With compound 7 for raw material, preparation method is with embodiment 7, and raw material dosage mol ratio is identical with embodiment 7, obtains white solid 3.2g, and productive rate is 85%. 1H NMR(300MHz,CDCl 3)：δ7.50-7.38(m,2H),7.03(d,J＝16.1Hz,1H),6.96(d,J＝16.2Hz,1H),6.93-6.86(m,2H),6.77(d,J＝2.1Hz,1H),6.41(d,J＝2.1Hz,1H),3.94(s,3H),3.89(s,3H),3.84(s,3H),3.84(s,3H). 13C NMR(75MHz,CDCl 3)：δ168.61,161.51,159.66,158.23,137.86,131.29,129.68,128.08,123.22,115.76,114.14,101.29,97.73,56.01,55.49,55.33,52.33.ESI-MS(m/z):329.4[M+H] +.
Embodiment 37:(E)-2-hydroxyl-4-methoxyl group-6-(4'-methoxy styryl) methyl benzoate (compound B-11 0)
With compd A 10 for raw material, preparation method is with embodiment 8, and raw material dosage mol ratio is identical with embodiment 8, obtains white solid, and productive rate is 90%.Obtain white solid 1.78g, productive rate is 92%. 1H NMR(300MHz,CDCl 3)：δ11.69(s,1H),7.57(d,J＝15.9Hz,1H),7.43(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),6.77(d,J＝15.9Hz,1H),6.62(d,J＝2.6Hz,1H),6.42(d,J＝2.6Hz,1H),3.94(s,3H),3.85(s,3H),3.84(s,3H). 13C NMR(75MHz,CDCl 3)：δ171.77,165.13,164.13,159.47,143.16,130.47,130.22,127.91,127.69,114.19,107.66,103.95,99.99,55.47,55.35,52.24.ESI-MS(m/z):337.2[M+Na] +.
Embodiment 38:(E)-2-hydroxyl-4-methoxyl group-6-(4'-methoxyl-styrene) benzoic synthesis (compd E 2)
By 315mg (1mmol) (E)-2,4-dimethoxy-6-(4'-methoxy styryl) methyl benzoate joins in the mixed solvent of ethanol 10mL and water 4mL, add 168mg (3mmol) KOH, heating reflux reaction 3h.Be cooled to room temperature, the hydrochloric acid with 10% adjusts pH to 2, separates out a large amount of white solid E2, filters, and collect filter cake, crude product obtains white solid 255mg through sherwood oil/acetone recrystallization, and productive rate is 85%. 1H NMR(300MHz,Acetone-d6)：δ12.01(s,1H),7.85(d,J＝16.1Hz,1H),7.53(d,J＝8.7Hz,2H),6.96(m,3H),6.74(d,J＝2.5Hz,1H),6.43(d,J＝2.6Hz,1H),3.90(s,3H),3.83(s,3H). 13C NMR(75MHz,Acetone-d6)：δ172.95,165.84,164.39,159.71,143.65,130.53,130.26,128.01,127.34,114.07,106.57,103.52,99.87,55.05,54.70.ESI-MS(m/z):301.3[M+H] +.
Embodiment 39:(E)-2-hydroxyl-4-methoxyl group-6-(4'-fluorostyryl) phenylformic acid E3
302mg (1mmol) compound 3b is joined in the mixed solvent of ethanol 10mL and water 4mL, adds 172mg (3mmol) KOH, heating reflux reaction 2h.Be cooled to room temperature, the hydrochloric acid dripping 10% adjusts pH to 2, separates out a large amount of white solid, filters, and collect filter cake, sherwood oil/acetone recrystallization obtains white solid 256mg, and productive rate is 89%. 1H NMR(300MHz,MeOD)：δ7.80(d,J＝16.0Hz,1H),7.60-7.43(m,2H),7.08(t,J＝8.8Hz,2H),6.84(d,J＝16.0Hz,1H),6.65(d,J＝2.5Hz,1H),6.41(d,J＝2.5Hz,1H),3.85(s,3H). 13CNMR(75MHz,MeOD)：δ172.93,164.98,164.06,162.41,142.91,134.05,129.53,128.99,128.03,114.99106.35,104.18,99.77,54.53.ESI-MS(m/z):289.3[M+H] +.
Embodiment 40: the Determination of Antibacterial Activity of cajanin analog
The compound of test comprises the compound of C series (C1, C2, C3, C4, C5, C6, C7, C8), D series (D1, D2, D3, D4, D5, D6, D7, D8), E (E1, E2, E3) series.
Adopt meat soup trace doubling dilution, measure the minimal inhibitory concentration (MIC) of cajanin derivatives bacteriostatic action, concrete operation method is as follows: (1) every hole on 96 orifice plates adds the liquid of 100 μ L different concns and the bacterium liquid of 100 μ L, final bacterial concentration is made to be 1 ~ 5cfu/ml, bacterium liquid is added as negative control (each 100 μ L of TSB substratum, bacterium liquid) using TSB broth culture, not add the TSB broth culture blank (TSB substratum 200 μ L) of bacterium liquid, 96 plate sealings are placed in 37 DEG C of constant incubators, hatch 20h.(2) be obviously grown to precondition with bacterium in negative control hole, by visual inspection, be the MIC (μ g/mL) of this medicine without the medicine minimum concentration obviously grown with bacterium in dosing metapore, test in triplicate parallel.The results are shown in Table 1 ~ 3, from table, Compound D 1, D2, D5 have stronger anti-microbial activity to streptococcus aureus, and MIC value is 2 ~ 4 μ g/mL.Compound D 1, D2, D5, D6 are 0.5 ~ 8 μ g/mL to the staphylococcic MIC of epidermis, are better than 16 μ g/mL of cajanin.To the anti-microbial effect of subtilis better, MIC is 0.5 ~ 2 μ g/mL for Compound D 1, D2, D3, D4, D5, D6, D7.Compound D 1, D2, D6, D7 all have good antibacterial effect to various methicillin-resistant staphylococcus aureus, and MIC value is 0.5 ~ 8 μ g/mL.The clinical commonly used drug such as penicillin, norfloxicin is better than to the antibacterial drug effect of MRSA, significant for the medicine finding antimicrobial agent.Therefore, theoretical and experimental studies results all shows, and cajanin is different from the new chemical entities of existing antibacterials completely as molecular structure, has good activity, very likely develop into antibacterial agent as new chemical entities for resistant organism.
Table 1 activity experiment bacterial strain uses therefor relevant information
Bacterial classification Latin language name Culture condition Numbering Pseudomonas
Streptococcus aureus Staphylococcus aureus Nutrient agar 37 DEG C, 24h ATCC25923 G +
Staphylococcus epidermidis Staphylococcus epidermidis Nutrient agar 37 DEG C, 24h ATCC12228 G +
Subtilis Bacillus subtilis Nutrient agar 37 DEG C, 24h ATCC6633 G +
Methicillin-resistant Staphylococcus aureus Methicillin-resistant S.a Nutrient agar 37 DEG C, 24h ATCC43300 G +
Intestinal bacteria Escherichia coli Nutrient agar 37 DEG C, 24h ATCC25922 G -
Common variation coccus Proteus vulgaris Nutrient agar 37 DEG C, 24h ATCC49101 G -
Pseudomonas aeruginosa Pesudomonas aeruginosa Nutrient agar 37 DEG C, 24h ATCC27853 G -
Note: the above examination bacterial classification that supplies derives from Guangdong Microbes Inst; G +: gram-positive microorganism; G -: Gram-negative bacteria.
Methicillin-resistant staphylococcus aureus MRSA 425055,513045,62202,51033,52056,515992,510019 is from Guangzhou General Hospital Guangzhou Military Command, and culture condition is identical with methicillin-resistant staphylococcus aureus MRSA43300.
Table 2 cajanin derivative is to the minimum inhibitory concentration (μ g/mL) of common bacteria
Compound S.a S.e B.s MRSA(43300) E.c P.v P.a
B1 ＞128 128 128 ＞128 ＞128 ＞128 128
B2 ＞128 128 128 ＞128 ＞128 ＞128 128
B3 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
B4 ＞128 ＞128 128 ＞128 ＞128 ＞128 ＞128
B5 128 128 ＞128 ＞128 ＞128 ＞128 128
B6 128 ＞128 ＞128 128 ＞128 ＞128 ＞128
B7 ＞128 ＞128 ＞128 128 64 128 ＞128
B9 ＞128 128 ＞128 ＞128 ＞128 ＞128 ＞128
B10 128 ＞128 ＞128 128 ＞128 ＞128 ＞128
C1 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C2 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C3 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C4 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C5 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C6 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C7 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C8 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
D1 4 1 0.5 1 64 ＞64 ＞64
D2 4 2 0.5 1 ＞128 ＞64 ＞64
D3 8 4 1 4 ＞128 ＞64 ＞64
D4 16 4 2 2 128 ＞64 ＞64
D5 2 8 0.5 32 ＞128 ＞64 ＞64
D6 16 0.5 2 2 ＞128 ＞64 ＞64
D7 16 8 0.5 2 ＞128 ＞64 ＞64
D8 64 32 64 32 ＞128 ＞64 ＞64
E1 64 64 64 64 ＞128 ＞128 ＞128
E2 128 128 128 128 ＞128 ＞128 ＞128
E3 128 64 64 128 ＞128 ＞128 ＞128
Cajanin 16 16 32 16 ＞128 ＞64 ＞64
Penicillin 2 2 2 32 64 ＞16 16
Norfloxicin 2 2 2 0.5 32 16 16
Table 3 cajanin derivative is to the minimum inhibitory concentration (MIC) of methicillin-resistant staphylococcus aureus
Compound 425055 513045 62202 51033 52056 515992 510019
B1 128 128 64 ＞128 ＞128 ＞128 ＞128
B2 ＞128 128 128 ＞128 ＞128 ＞128 128
B3 ＞128 ＞128 ＞128 ＞128 ＞128 128 ＞128
B4 ＞128 ＞128 128 ＞128 ＞128 ＞128 ＞128
B5 128 128 ＞128 ＞128 ＞128 ＞128 128
B6 128 ＞128 ＞128 128 ＞128 ＞128 ＞128
B7 ＞128 ＞128 ＞128 128 ＞128 64 ＞128
B9 ＞128 64 ＞128 ＞128 ＞128 ＞128 ＞128
B10 128 ＞128 ＞128 128 ＞128 ＞128 ＞128
C1 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C2 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C3 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C4 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C5 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C6 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C7 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
C8 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128 ＞128
D1 0.5 2 0.5 1 2 2 2
D2 2 2 0.5 1 0.5 1 1
D3 4 8 1 4 2 8 2
D4 4 4 2 0.5 2 4 1
D5 0.5 0.5 8 32 8 8 4
D6 4 0.5 4 2 2 4 4
D7 1 8 0.5 1 4 1 2
D8 32 32 64 32 16 32 32
E1 64 64 64 64 128 128 128
E2 128 ＞128 128 ＞128 ＞128 ＞128 ＞128
E3 128 64 64 128 ＞128 128 128
Cajanin 16 16 8 16 16 32 32
Penicillin 32 32 32 32 64 32 32
Norfloxicin 4 4 2 0.5 4 4 2
From experimental result, cajanin analogue of the present invention has good anti-microbial activity to gram-positive microorganism, especially to methicillin-resistant staphylococcus aureus, is better than positive control drug.This is be found first time in this compounds.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (6)

1. a cajanin analog, is characterized in that having structure shown in formula I:
Wherein, R 1for-H or-CH 3;
R 2for-H, isopentene group or geranyl;
R 3for-CH 3or
R 4for-H ,-F ,-Cl ,-OCH 3,-CF 3or-CN, and do not limit it in the nuclear substituted number of benzene.
2. cajanin analog according to claim 1, is characterized in that having following shown structure:
3. the application of the cajanin analog according to any one of claim 1 ~ 2 in preparation antibacterials.
4. the cajanin analog according to any one of claim 1 ~ 2 is preparing the application in anti-Staphylococcus aureus medicine.
5. the application of cajanin analog according to claim 3 in preparation antibacterials, is characterized in that: described medicine refers to containing at least one in described cajanin analog or its pharmaceutical salts and solvate.
6. the application of cajanin analog according to claim 3 in preparation antibacterials, is characterized in that: described medicine can contain one or more pharmaceutically acceptable carrier or vehicle.
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CN111039983A (en) * 2019-12-19 2020-04-21 赵洁 Preparation method and application of antibacterial drug
CN111039983B (en) * 2019-12-19 2022-04-15 赵洁 Preparation method and application of antibacterial drug
CN111494364A (en) * 2020-06-19 2020-08-07 中南民族大学 Application of isopentenyl substituted phenol compound in resisting staphylococcus aureus and methicillin-resistant staphylococcus aureus
CN111494364B (en) * 2020-06-19 2021-02-12 中南民族大学 Application of isopentenyl substituted phenol compound in resisting staphylococcus aureus and methicillin-resistant staphylococcus aureus
CN114075107A (en) * 2020-08-17 2022-02-22 暨南大学 Cajanin derivatives and application thereof in preparation of antibacterial drugs

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