CN104926761B - The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace - Google Patents

The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace Download PDF

Info

Publication number
CN104926761B
CN104926761B CN201410098808.8A CN201410098808A CN104926761B CN 104926761 B CN104926761 B CN 104926761B CN 201410098808 A CN201410098808 A CN 201410098808A CN 104926761 B CN104926761 B CN 104926761B
Authority
CN
China
Prior art keywords
compound
cdcl
nmr
isocyanates
yunnan province
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410098808.8A
Other languages
Chinese (zh)
Other versions
CN104926761A (en
Inventor
张卫东
孙青龑
单磊
苏娟
李慧梁
沈云亨
徐希科
邵文浩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Second Military Medical University SMMU
Original Assignee
Second Military Medical University SMMU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Second Military Medical University SMMU filed Critical Second Military Medical University SMMU
Priority to CN201410098808.8A priority Critical patent/CN104926761B/en
Publication of CN104926761A publication Critical patent/CN104926761A/en
Application granted granted Critical
Publication of CN104926761B publication Critical patent/CN104926761B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to pharmaceutical technology field, the invention provides the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind isocyanate, benzoic acid and cinnamic acid replace, present invention also offers above-mentioned the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue synthetic method and the application in anti-inflammatory drug is prepared.The compounds of this invention Jing cells anti-inflammatory activity and cytotoxicity experiment, as a result prove, the compounds of this invention has the activity for suppressing macrophage RAW264.7 generation NO well；And cytotoxicity is relatively low.Therefore, the compounds of this invention has preferable anti-inflammatory activity, and there are low toxicity compounds, can be used as new anti-inflammatory drug.

Description

The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates, benzoic acid and cinnamic acid replace and Its synthesis and application
Technical field
The present invention relates to pharmaceutical technology field, and in particular to the southern regions of the Yunnan Province that a kind isocyanate, benzoic acid and cinnamic acid replace Foreign ear chrysanthemum lactone analogue, and its synthetic method and the application in anti-inflammatory drug is prepared.
Background technology
Compositae (Compositae) Inula (Inula L.) plant there are about 100 kinds, be distributed mainly on Mediterranean Region, It is also distributed in other areas in Europe, Africa and Asia.This platymiscium has more than 20 kinds and most mutation in China, wherein more than half Plant have medicinal record（Chinese Plants will editorial board of the Chinese Academy of Sciences, Chinese Plants will [M], Beijing：Scientific publication Society, 1979,75:248-281）.Chinese scholars priority isolated flavone, sesquiterpene lactoness, terpenoid etc. from the platymiscium The compound of structure type（Zhao YM,Zhang ML,Shi QW,Kiyota H.Chemical constituents of plants from the genus Inula.Chemistry&Biodiversity2006;3:371-383）.Sesquiterpene lactoness It is the characteristic chemical constituent of this platymiscium, and main active component has antiinflammatory, antitumor, antiviral, anthelmintic parasite killing, immunity Various effects such as suppression.Document shows that the alpha-methylene in such molecular structure of compounds-gamma lactone fragment is pharmacophoric group, The fragment can be with some nucleophilic groups, and the sulfydryl fragment of such as cysteine occurs Michael addition reaction, so as to produce medicine Reason is acted on（S.M.Kupchan,M.A.Eakin,A.M.Thomas.Tumor inhibitors.69.Structure- cytotoxicity relations among the sesquiterpene lactones,Journal of Medicinal Chemistry1971;14;1147-1152）.Sesquiterpene lactoness are also as its simple structure, and have various mother nucleus structure classes Type, can be used as the lead compound of research and development medicine.
China's endemic plant Inula wissmanniana (Inula wissmanniana Hand.-Mazz.) is Inulaplants, Yunnan Province is commonly called as " torch stalk ", is undershrub, produces south of Yunnan (Yuanjiang River, screen side).It is born in low mountain Kai Kuang hillside fields, height above sea level 1200 ～1650 meters.
The present inventor is devoted for years to the correlational study of chemical composition and biological activity in Inula wissmanniana.At present from Yunnan Isolated 28 sesquiterpenoidss compositions, wherein Inula wissmanniana total extract and 6 Germacrane Sesquiterpenoids in southern Herba Inulae cappae Lactone has good antiinflammatory and anti-anti-tumor activity, has applied for Chinese patent：Chinese patent application CN201310014911.5, entitled Inula wissmanniana extract and its preparation and the application in anti-inflammatory drug is prepared, Publication No. CN103058970A；Chinese patent application CN201310014913.4, entitled Inula wissmanniana extract And its prepare and the application in antitumor drug is prepared, Publication No. CN103102336A.
The present inventor has applied for Chinese patent CN201310560385.2, entitled " the southern regions of the Yunnan Province sheep in 20131112 again The application of ear chrysanthemum lactone A and its derivant in anti-inflammatory drug is prepared ", described Inula wissmanniana lactone A and its derivant, its Chemical constitution is as shown in formula A：
It is relevant the new chemical composition with biological activity to be searched out from Inula wissmanniana and in Inula wissmanniana Ester carries out the research emphasis that structure of modification is this area.
The content of the invention
It is an object of the invention to structure of modification is carried out to Inula wissmanniana lactone, it is more preferable to obtain a class anti-inflammatory activity The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue is the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates, benzoic acid and cinnamic acid replace；This Bright another object is to provide the synthetic method of such the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue；The third object of the present invention is to provide this Application of the ear chrysanthemum lactone analogue in anti-inflammatory drug is prepared of class the southern regions of the Yunnan Province ocean.
The present inventor has carried out structure of modification to Inula wissmanniana lactone A, is retaining pharmacophore alpha-methylene-gamma lactone On the basis of fragment, using the phenyl isocyanate of different substituents, benzoic acid and cinnamic acid and synthesis the southern regions of the Yunnan Province ocean ear chrysanthemum lactone During the intermediate of hydroxyl there is esterification, synthesized that 32 isocyanates replace, 8 benzoic acid replace, 10 meat The Inula wissmanniana lactone analog that cinnamic acid replaces, and these compounds have been carried out with extracorporeal anti-inflammatory activity and cytotoxicity reality Test, as a result show majority of compounds anti-inflammatory activity very well, and have high activity and hypotoxicity concurrently.
At present, isocyanates, benzoic acid, the Inula wissmanniana lactone analog chemosynthesis of cinnamic acid replacement and medicine be there is no The document report of reason activity, also has no and the Inula wissmanniana lactone isocyanates in the present invention, benzoate, cinnamate derivative Like the relevant report of thing preparation method, purposes.
A first aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear chrysanthemum that a kind of isocyanates, benzoic acid or cinnamic acid replace Lactone analogue, including its enantiomeric forms, its chemical constitution is as shown in formula 1, formula 2 or formula 3：
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates replace, including its enantiomer, selected from following arbitrary：
In formula 1, R1 is respectively：
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of benzoic acid replaces, including its enantiomer, selected from following arbitrary：
In formula 2, R2 is respectively：
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of cinnamic acid replaces, including its enantiomer, selected from following arbitrary：
In formula 3, R3 is respectively：
A second aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear that above-mentioned isocyanates, benzoic acid or cinnamic acid replace The preparation method of chrysanthemum lactone analogue.
Synthetic route is：
Reactions steps are as follows：
Dicyclohexylcarbodiimide (DCC) and ether is dissolved in dimethylamino naphthyridine (DMAP), under the conditions of subzero 30 DEG C by It is added dropwise to the diethyl ether solution of acetylenecarboxylic acid, cis-butenediol.After completion of dropping, room temperature reaction obtains compound 1 in 12 hours.In catalysis Agent 1, under the effect of 5- cyclo-octadiene chlorine rhodium dimerization, silver hexafluoroantimonate and chiral ligand dinaphthalene diphenyl phosphine (R-BINAP, S-BINAP), Compound 1 can change into the compound 2r and 2s of two kinds of configurations of R, S respectively.Compound 2r is with 2s by borane reduction into compound 3r and 3s, compound 3r and 3s substituted isocyanates different from phenyl ring, benzoic acid, Cortex Cinnamomi acid reaction can obtain targeted Compound 4r, 4s, 5s, 6s.
A third aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear that above-mentioned isocyanates, benzoic acid or cinnamic acid replace Application of the chrysanthemum lactone analogue in anti-inflammatory drug is prepared.
50 compound 4r-1～16,4s-1～16 to present invention synthesis, 5s-1～8,6s-1～10 carry out cell and resist Scorching activity and cytotoxicity experiment, as a result prove, there is such compound suppression macrophage RAW264.7 well to produce NO Activity；In cytotoxicity, all toxicity of compound are all relatively low, toxicity IC50It is all higher than 20 μM.
Therefore, such compound has preferable anti-inflammatory activity, and has hypotoxicity concurrently, can to prepare that anti-inflammatory drug provides Energy.
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates of the present invention, benzoic acid or cinnamic acid replace prepares antiinflammatory Medicine, is as active component and routine by the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of isocyanates, benzoic acid or cinnamic acid replacement Pharmaceutical composition made by pharmaceutical carrier.
Described pharmaceutical composition can be tablet, dispersible tablet, buccal tablet, oral cavity disintegration tablet, slow releasing tablet, capsule, soft capsule, Drop pill, granule, injection, injectable powder or aerosol etc..
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 4r-1～16 Pharmaceutical composition.
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 4s-1～16 Pharmaceutical composition.
Pharmaceutical composition of the present invention is the medicine being made up of as active component and pharmaceutic adjuvant compound 5s-1～8 Compositions.
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 6s-1～10 Pharmaceutical composition.
Present invention firstly discloses the change of the Inula wissmanniana lactone analog of isocyanates, benzoic acid, cinnamic acid replacement Synthetic method is learned, and there is provided their cell anti-inflammatory activity and cell toxicity data, new anti-inflammatory drug is provided for clinic Probability, brings glad tidings to patient, has larger clinical value and higher social benefit.
The present invention provides new medicine for the treatment of inflammation, has larger clinical value.
Description of the drawings
Fig. 1：The single crystal diffraction structure of compound 4r-3；
Fig. 2：The single crystal diffraction structure of compound 4s-8.
Specific embodiment
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.
Agents useful for same of the present invention and raw material are commercially available or can prepare by literature method.Unreceipted tool in the following example The experimental technique of concrete conditions in the establishment of a specific crime, generally according to normal condition, or according to the condition proposed by manufacturer.
Embodiment 1：The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 32 isocyanates replacements
Synthetic route is：
Compound 1：Dicyclohexylcarbodiimide (DCC) (2.79g, 13.5mmol) and to dimethylamino naphthyridine (DMAP) (0.12g, 0.09mmol) is dissolved in ether, and acetylenecarboxylic acid (0.93g, 13.2mmol), maleic are added dropwise under the conditions of subzero 30 DEG C The diethyl ether solution of glycol (1.05g, 12.0mmol).Room temperature reaction 12 hours after completion of dropping, after reaction terminates, saturated ammonium chloride Solution is quenched, and organic faciess are extracted three times with ether, merges organic faciess, and anhydrous sodium sulfate drying, concentrated post obtain compound 1 (76%) 1.41g is yellow oil.
Compound 2s：1,5- cyclo-octadiene chlorine rhodium dimerization (50.2mg, 0.102mol), silver hexafluoroantimonate (70.0mg, 0.204mol) add three-necked bottle, argon protection, used syringe that 10ml acetone is added in bottle, 20 minutes is stirred at room temperature, argon Protection is lower to filter, and filtrate continues to be stirred at room temperature 20 minutes with chiral ligand S- dinaphthalene diphenyl phosphines (127mg, 0.204mol), will To solution be added in 1, the 2- dichloroethane solutions of compound 1 (1.14g, 8.14mmol), 21 hours are stirred at room temperature, instead The concentrated post of liquid is answered, (59%) 0.67g is yellow oil to obtain compound 2s.Compound 2r is obtained with same method, chiral Part changes R- dinaphthalene diphenyl phosphines into.
Compound 3s：At 0 DEG C to compound 2s (39mg, 0.28mmol) tetrahydrofuran solution Deca borine tetrahydrofuran Solution (0.31mL, 1M in THF, 0.31mmol), response time are 30 minutes, and reaction terminates rear saturated ammonium chloride solution and quenches Go out, organic faciess are extracted with ethyl acetate three times, merge organic faciess, anhydrous sodium sulfate drying, be concentrated to give compound 3s (0.26g, 65%) it is yellow oil.
Compound 4s-1～16 and 4r-1～16 universal synthesis method：Under room temperature, compound 3s or 3r is different from phenyl ring takes The isocyanates (1.2eq) in generation are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows：
Compound 1：Yellow oil;
1H NMR(500MHz,CDCl3)δ5.82(dt,J=11.6,6.4Hz,1H),5.59(dt,J=11.2,7.0Hz, 1H),4.73(d,J=7.0Hz,2H),4.20(d,J=6.3Hz,2H),2.83(s,1H).
13C NMR(125MHz,CDCl3)δ152.73,134.57,124.26,75.28,74.55,61.85,58.59.
HR-ESI-MS calcd for C7H8O3[M+H]+141.1366,found141.0531.
Compound 2s：Yellow oil;
1H NMR(600MHz,CDCl3)δ9.82(s,1H),6.31(d,J=2.9Hz,1H),5.65(d,J=2.6Hz,1H), 4.65(dd,J=9.3,8.6Hz,1H),3.92(dd,J=9.4,5.9Hz,1H),3.58(ddt,J=11.2,5.7,3.0Hz, 1H),2.99(dd,J=19.0,5.1Hz,1H),2.79(dd,J=19.0,8.7Hz,1H).
13C NMR(150MHz,CDCl3)δ199.15,170.23,137.45,123.00,77.16,71.14,48.33, 33.18.
HR-ESI-MS calcd for C7H9O3[M+H]+141.1366,found141.0537.
Compound 3s：Yellow oil;
1H NMR(500MHz,CDCl3)δ6.27(d,J=2.8Hz,1H),5.63(d,J=2.5Hz,1H),4.55–4.51 (m,1H),4.07(dd,J=9.1,5.9Hz,1H),3.79–3.72(m,2H),3.29–3.23(m,1H),1.94(ddd,J= 14.0,11.4,5.6Hz,1H),1.81–1.73(m,1H).
13C NMR(125MHz,CDCl3)δ171.05,138.35,122.23,71.69,60.03,36.53,36.13.
HR-ESI-MS calcd for C7H11O3[M+H]+143.1525,found143.0702.
Compound 4s-1：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and phenyl isocyanate under room temperature (1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.1mg, yield 70.5%.
1H NMR(500MHz,CDCl3)δ7.38(d,J=7.4Hz,2H),7.31(t,J=8.0Hz,2H),7.08(t,J= 7.4Hz,1H),6.31(d,J=2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.35–4.22 (m,2H),4.07(dd,J=9.0,5.6Hz,1H),3.23–3.20(m,1H),2.10–2.02(m,1H),1.98–1.90(m, 1H).
13C NMR(125MHz,CDCl3)δ170.62,153.33,137.83,129.24,123.90,122.65, 118.91,71.06,62.27,36.40,33.01.
HR-ESI-MS calcd for C15H16NO4[M+H]+262.2812,found262.2826.
Compound 4r-1：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 52.2mg, Yield is 80%.
1H NMR(500MHz,CDCl3)δ7.38(d,J=7.5Hz,2H),7.32(t,J=8.0Hz,2H),7.09(t,J= 7.3Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.4Hz,1H),4.53(t,J=8.6Hz,1H),4.33–4.24 (m,2H),4.08(dd,J=9.0,5.6Hz,1H),3.22(ddd,J=8.2,5.6,2.7Hz,1H),2.10–2.05(m,1H), 1.96–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.61,153.31,137.83,137.65,129.25,123.91, 122.66,118.89,71.05,62.27,36.40,33.03.
HR-ESI-MS calcd for C15H16NO4[M+H]+262.2812,found262.2819.
Compound 4s-2：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and 2,4 difluorobenzene base isocyanide under room temperature Acid esters (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 56.5mg, yield 76.1%.
1H NMR(500MHz,CDCl3)δ7.94(s,1H),6.86(d,J=3.4Hz,1H),6.84(dd,J=7.7, 4.5Hz,1H),6.29(d,J=2.2Hz,1H),5.66(d,J=1.2Hz,1H),4.50(t,J=8.4Hz,1H),4.31–4.21 (m,2H),4.07–4.03(m,1H),3.21(s,1H),2.07–2.03(m,1H),1.93–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,158.42(d,J=251.1Hz),153.17,153.57–151.37 (m),137.70,122.60,122.38,121.72,111.34(dd,J=21.9,3.3Hz),104.00–103.54(m), 70.93,62.62,36.22,32.87.
HR-ESI-MS calcd for C14H14F2NO4[M+H]+298.2621,found298.2627.
Compound 4r-2：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 55.2mg, Yield is 74.3%.
1H NMR(500MHz,CDCl3)δ7.97(s,1H),6.87(dd,J=5.2,3.2Hz,1H),6.75(s,1H), 6.32(d,J=3.0Hz,1H),5.67(d,J=2.2Hz,1H),4.52(t,J=8.5Hz,1H),4.40–4.22(m,2H),4.07 (d,J=5.7Hz,1H),3.22(s,1H),2.10–2.05(m,1H),1.97–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,158.45(d,J=246.2Hz),153.17,153.76–151.37 (m),137.70,122.61,122.39,121.71,111.35(dd,J=21.9,3.3Hz),103.78(t,J=24.9Hz), 70.93,62.63,36.23,32.88.
HR-ESI-MS calcd for C14H14F2NO4[M+H]+298.2621,found298.2628.
Compound 4s-3：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and parachlorobenzyl isocyanic ester under room temperature (1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Extraction, merges organic faciess, and the concentrated post of drying obtains product 60.6mg, yield 82.2%.
1H NMR(500MHz,CDCl3)δ7.33(d,J=8.2Hz,2H),7.28(d,J=8.9Hz,2H),6.33(d,J= 2.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,1H),4.33–4.23(m,2H),4.08(dd,J= 9.1,5.5Hz,1H),3.25–3.20(m,1H),2.11–2.04(m,1H),1.98–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.54,153.12,137.81,136.25,129.29,122.70, 120.15,70.95,62.45,36.39,33.05.
HR-ESI-MS calcd for C14H14ClNO4Na[M+Na]+318.7078,found318.7073.
Compound 4r-3：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 58.7mg, Yield is 79.6%.
1H NMR(500MHz,CDCl3)δ7.34(d,J=8.1Hz,2H),7.28(s,2H),6.32(d,J=2.6Hz,1H), 5.67(d,J=2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.23(m,2H),4.08(dd,J=9.0,5.5Hz, 1H),3.26–3.17(m,1H),2.11–2.05(m,1H),1.97–1.92(m,1H).
13C NMR(125MHz,CDCl3)δ170.61,153.16,137.81,136.32,129.24,128.89, 122.68,120.14,71.01,62.44,36.41,32.96.
HR-ESI-MS calcd for C14H14ClNO4Na[M+Na]+318.7078,found318.7069.
The single crystal diffraction structure of compound 4r-3 is as shown in Figure 1.
Compound 4s-4：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and p-bromophenyl isocyanates under room temperature (1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Extraction, merges organic faciess, and the concentrated post of drying obtains product 72.8mg, yield 85.9%.
1H NMR(500MHz,CDCl3)δ7.41(d,J=8.7Hz,2H),7.29(d,J=8.2Hz,2H),6.31(d,J= 2.7Hz,1H),5.67(d,J=2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.22(m,2H),4.07(dd,J= 9.1,5.6Hz,1H),3.21(ddd,J=8.1,5.5,2.6Hz,1H),2.14–2.00(m,1H),1.92(ddd,J=14.2, 7.9,5.7Hz,1H).
13C NMR(125MHz,CDCl3)δ170.63,153.12,137.79,136.88,132.1,122.68,120.44, 116.34,71.03,62.45,36.41,32.92.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1726.
Compound 4r-4：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 78.7mg, Yield is 92.7%.
1H NMR(500MHz,CDCl3)δ7.42(d,J=8.8Hz,2H),7.28(d,J=8.3Hz,2H),6.32(d,J= 2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.33–4.24(m,2H),4.08(dd,J= 9.1,5.5Hz,1H),3.22(ddd,J=8.2,5.5,2.6Hz,1H),2.07(ddd,J=14.3,12.0,5.6Hz,1H), 1.98–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.57,153.09,137.80,136.82,132.21,122.69, 120.45,70.96,62.45,36.39,33.00.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1725.
Compound 4s-5：Yellow solid；Under room temperature compound 3s (35.5mg, 0.25mmol) with to iodobenzene based isocyanate (1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Extraction, merges organic faciess, and the concentrated post of drying obtains product 75.1mg, yield 77.6%.
1H NMR(500MHz,CDCl3)δ7.60(d,J=8.2Hz,2H),7.17(d,J=7.5Hz,2H),6.32(s,1H), 5.67(s,1H),4.52(t,J=8.4Hz,1H),4.27(d,J=21.2Hz,2H),4.14–3.98(m,1H),3.22(s,1H), 2.08–2.04(m,1H),1.93(s,1H).
13C NMR(125MHz,CDCl3)δ170.60,153.03,138.14,137.80,137.56,122.70, 120.74,86.81,71.01,62.46,36.40,32.97.
HR-ESI-MS calcd for C14H15INO4[M+H]+387.1698,found387.1692.
Compound 4r-5：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 75.2mg, Yield is 77.7%.
1H NMR(500MHz,CDCl3)δ7.61(d,J=8.8Hz,2H),7.17(d,J=8.2Hz,2H),6.32(d,J= 2.6Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.36–4.18(m,2H),4.08(dd,J= 9.1,5.4Hz,1H),3.30–3.14(m,1H),2.31–2.00(m,1H),1.96–1.93(m,1H).
13C NMR(125MHz,CDCl3)δ170.57,153.04,138.15,137.80,137.54,122.70, 120.73,86.83,70.97,62.46,36.39,32.99.
HR-ESI-MS calcd for C14H15INO4[M+H]+387.1698,found387.1689.
Compound 4s-6：Yellow oil；Compound 3s (35.5mg, 0.25mmol) and 2- methyl -6- isopropyls under room temperature Base phenyl isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution Washing, dichloromethane extraction merge organic faciess, and the concentrated post of drying obtains product 58.6mg, yield 73.9%.
1H NMR(500MHz,CDCl3)δ7.20(d,J=7.6Hz,1H),7.17(d,J=7.3Hz,1H),7.09(d,J= 7.2Hz,1H),6.27(d,J=60.1Hz,1H),5.59(d,J=106.4Hz,1H),4.55(t,J=8.4Hz,1H),4.40– 4.26(m,2H),4.16–4.04(m,1H),3.24(s,1H),3.18–3.08(m,1H),2.26(s,3H),2.04(s,1H), 1.74–1.69(m,1H),1.20(s,6H).
13C NMR(125MHz,CDCl3)δ170.79,154.94,146.58,138.18,136.79,132.14, 128.79,128.47,124.08,122.85,71.33,62.65,36.72,33.55,28.95,23.87,18.87.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3871.
Compound 4r-6：Yellow oil；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 60.2mg, yield are 76.0%.
1H NMR(500MHz,CDCl3)δ7.21(d,J=6.4Hz,1H),7.17(d,J=7.1Hz,1H),7.09(d,J= 7.0Hz,1H),6.28(d,J=60.0Hz,1H),5.60(d,J=106.6Hz,1H),4.56(s,1H),4.36–4.26(m, 2H),4.11(s,1H),3.24(s,1H),3.14(d,J=6.1Hz,1H),2.26(s,3H),2.09(s,1H),1.72(s, 1H),1.20(s,6H).
13C NMR(125MHz,CDCl3)δ170.54,154.69,146.33,137.92,136.53,131.89, 128.53,128.22,123.83,122.60,71.08,62.39,36.46,33.30,28.68,23.62,18.62.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3868.
Compound 4s-7：Yellow solid；Under room temperature compound 3s (35.5mg, 0.25mmol) with to n-butoxycarbonyl benzene Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 80.5mg, yield 89.2%.
1H NMR(500MHz,CDCl3)δ7.99(d,J=8.6Hz,1H),7.47(d,J=8.5Hz,1H),6.32(d,J= 2.5Hz,1H),5.67(d,J=2.2Hz,1H),4.52(t,J=8.6Hz,1H),4.42–4.22(m,2H),4.08(dd,J= 9.1,5.5Hz,1H),3.32–3.12(m,1H),2.09–2.05(m,1H),1.96–1.92(m,1H),1.78–1.68(m, 1H),1.52–1.41(m,1H),0.97(t,J=7.4Hz,1H).
13C NMR(125MHz,CDCl3)δ170.67,166.39,152.89,141.98,137.77,131.03, 125.58,122.77,117.82,71.02,64.92,62.54,36.38,32.92,30.91,19.39,13.88.
HR-ESI-MS calcd for C19H23NaNO6[M+Na]+384.3788,found384.3779.
Compound 4r-7：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 77.2mg, Yield is 85.5%.
1H NMR(500MHz,CDCl3)δ8.00(d,J=7.9Hz,2H),7.46(d,J=7.9Hz,2H),6.33(d,J= 1.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,1H),4.35–4.25(m,2H),4.09(dd,J= 9.1,5.4Hz,1H),3.23(dd,J=6.6,4.2Hz,1H),2.09(dd,J=14.4,5.8Hz,1H),1.95(dd,J= 14.4,7.2Hz,1H),1.77–1.72(m,2H),1.47(dd,J=15.0,7.5Hz,2H),0.97(t,J=7.4Hz,3H).
13C NMR(125MHz,CDCl3)δ170.68,166.39,152.89,141.99,137.76,131.03, 125.58,122.78,117.82,71.04,64.92,62.55,36.38,32.93,30.91,19.40,13.89.
HR-ESI-MS calcd for C19H23NaNO6[M+Na]+384.3788,found384.3776.
Compound 4s-8：Yellow solid；Under room temperature compound 3s (35.5mg, 0.25mmol) with to ethylphenyl Carbimide. Ester (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Alkane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 59.7mg, yield 82.6%.
1H NMR(500MHz,CDCl3)δ7.28(d,J=6.2Hz,1H),7.14(d,J=8.4Hz,2H),6.31(d,J= 2.7Hz,1H),5.67(d,J=2.3Hz,1H),4.52(t,J=8.3Hz,1H),4.33–4.22(m,2H),4.10–4.03(m, 1H),3.21(s,1H),2.61(q,J=7.6Hz,2H),2.09–2.05(m,1H),1.93–1.90(m,1H),1.21(t,J= 7.6Hz,3H).
13C NMR(125MHz,CDCl3)δ170.60,153.46,137.85,135.21,128.56,122.62, 121.48,119.09,71.07,62.21,36.41,33.06,28.32,15.77.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3351.
The single crystal diffraction structure of compound 4s-8 is as shown in Figure 2.
Compound 4r-8：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 56.7mg, Yield is 79.7%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.6Hz,2H),7.15(d,J=8.4Hz,2H),6.32(d,J= 2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.4Hz,1H),4.33–4.21(m,2H),4.09–4.05(m, 1H),3.23–3.20(m,1H),2.61(q,J=7.6Hz,2H),2.10–2.04(m,1H),1.96–1.88(m,1H),1.21 (t,J=7.6Hz,3H).
13C NMR(125MHz,CDCl3)δ170.59,153.50,140.07,137.85,135.20,128.57, 122.62,119.08,71.06,62.21,36.41,33.07,28.33,15.77.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3349.
Compound 4s-9：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and bis- trifluoromethylbenzenes of 3,5- under room temperature Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 80.6mg, yield 81.2%.
1HNMR(500MHz,CDCl3)δ7.93(s,1H),7.57(s,1H),6.33(d,J=2.6Hz,1H),5.69(d,J= 2.3Hz,1H),4.55(t,J=8.6Hz,1H),4.37–4.30(m,2H),4.11(dd,J=9.1,5.5Hz,1H),3.29– 3.21(m,1H),2.16–2.08(m,1H),2.00–1.94(m,1H).
13C NMR(125MHz,CDCl3)δ170.77,152.90,139.48,137.76,132.64(q,J=33.5Hz), 122.85,122.13,118.46,117.02,71.02,62.97,36.50,32.80.
HR-ESI-MS calcd for C16H14F6NO4[M+H]+398.2771,found398.2762.
Compound 4r-9：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 76.7mg, Yield is 77.3%.
1HNMR(500MHz,CDCl3)δ7.92(s,2H),7.57(s,1H),6.34(d,J=2.7Hz,1H),5.69(d,J= 2.4Hz,1H),4.56–4.52(m,1H),4.38–4.30(m,2H),4.11(dd,J=9.2,5.4Hz,1H),3.26–3.23 (m,1H),2.15–2.05(m,1H),2.00–1.95(m,1H).
13C NMR(125MHz,CDCl3)δ170.76,152.89,139.47,137.76,132.84–132.06(m), 122.84,122.12,118.46,117.03,71.00,62.96,36.49,32.81.
HR-ESI-MS calcd for C16H14F6NO4[M+H]+398.2771,found398.2765.
Compound 4s-10：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and 3,4- 3,5-dimethylphenyls under room temperature Isocyanates (1.2eq) are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, Dichloromethane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 60.6mg, yield 83.9%.
1H NMR(500MHz,CDCl3)δ7.16(s,1H),7.06(d,J=7.7Hz,2H),6.32(d,J=2.7Hz,1H), 5.67(d,J=2.5Hz,1H),4.52(s,1H),4.40–4.18(m,2H),4.07(s,1H),3.22(s,1H),2.24(s, 3H),2.21(s,3H),2.11–2.02(m,1H),1.97–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.55,153.50,137.85,137.53,135.22,130.21, 120.41,118.75,116.56,71.09,62.20,36.42,33.11,20.03,19.20.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3339.
Compound 4r-10：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 54.5mg, yield are 75.4%.
1H NMR(500MHz,CDCl3)δ7.16(s,1H),7.07(s,2H),6.32(d,J=2.7Hz,1H),5.67(d,J =2.4Hz,1H),4.53(t,J=8.4Hz,1H),4.31–4.22(m,2H),4.09–4.06(m,1H),3.22(s,1H),2.24 (s,3H),2.22(s,3H),2.10–2.04(m,1H),1.95–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.81,153.76,138.10,137.78,135.47,130.47, 122.88,120.66,119.01,116.81,71.34,62.46,36.68,33.37,20.28,19.46.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3337.
Compound 4s-11：Dark red oil；Compound 3s (35.5mg, 0.25mmol) and cumic aldehyde under room temperature Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 60.3mg, yield 79.6%.
1H NMR(500MHz,CDCl3)δ7.29(d,J=6.4Hz,2H),7.17(d,J=8.4Hz,2H),6.31(d,J= 2.6Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.2Hz,1H),4.34–4.20(m,2H),4.07(d,J= 5.4Hz,1H),3.21(s,1H),2.89–2.85(m,1H),2.07–2.04(m,1H),1.92–1.87(m,1H),1.22(d,J =6.9Hz,6H).
13C NMR(125MHz,CDCl3)δ170.59,153.49,144.69,137.85,135.26,127.12, 122.61,119.12,71.07,62.20,36.41,33.62,33.06,24.14.
HR-ESI-MS calcd for C17H22NO4[M+H]+304.3609,found304.3619.
Compound 4r-11：Dark red oil；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 62.6mg, yield are 82.6%.
1H NMR(500MHz,CDCl3)δ7.29(d,J=5.3Hz,2H),7.17(d,J=8.4Hz,2H),6.32(d,J= 2.5Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.3Hz,1H),4.34–4.20(m,2H),4.06(d,J= 7.0Hz,1H),3.21(s,1H),2.90–2.85(m,1H),2.08–2.04(m,1H),1.94–1.90(m,1H),1.23(d,J =6.9Hz,6H).
13C NMR(125MHz,CDCl3)δ170.57,153.45,144.69,137.85,135.25,127.14, 122.61,119.14,71.06,62.20,36.41,33.63,33.08,24.14.
HR-ESI-MS calcd for C17H22NO4[M+H]+304.3609,found304.3616.
Compound 4s-12：Yellow oil；Compound 3s (35.5mg, 0.25mmol) and 2- fluorophenyl isocyanides under room temperature Acid esters (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 52.3mg, yield 75.0%.
1HNMR(500MHz,CDCl3)δ8.04(s,1H),7.12(dd,J=15.0,7.1Hz,1H),7.07(dd,J= 11.0,1.5Hz,1H),6.85(s,1H),6.33(d,J=2.7Hz,1H),5.69(d,J=2.4Hz,1H),4.53(t,J= 8.6Hz,1H),4.32–4.27(m,2H),4.07(dd,J=9.1,5.5Hz,1H),3.27–3.20(m,1H),2.11–2.04 (m,1H),2.01–1.84(m,1H).
13C NMR(125MHz,CDCl3)δ170.44,153.01,137.74,126.14(d,J=10.0Hz),124.80 (d,J=3.2Hz),123.98,122.73,120.49,115.09(d,J=19.1Hz),70.97,62.56,36.27,33.04.
HR-ESI-MS calcd for C14H15FNO4[M+H]+280.2716,found280.2722.
Compound 4r-12：Yellow oil；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 53.6mg, yield are 76.8%.
1HNMR(500MHz,CDCl3)δ8.04(s,1H),7.10(dd,J=18.9,4.6Hz,1H),7.06(d,J= 1.3Hz,1H),6.86(s,1H),6.33(d,J=2.6Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz, 1H),4.35–4.23(m,2H),4.10–4.05(m,1H),3.26–3.20(m,1H),2.12–2.06(m,1H),1.99–1.89 (m,1H).
13C NMR(125MHz,CDCl3)δ170.45,153.02,137.73,126.16,124.78(d,J=3.3Hz), 123.98,122.72,120.44,115.08(d,J=19.1Hz),70.97,62.56,36.26,33.02.HR-ESI-MS calcd for C14H15FNO4[M+H]+280.2716,found280.2725.
Compound 4s-13：Brown solid；Under room temperature, compound 3s (35.5mg, 0.25mmol) is different with p-methoxyphenyl Cyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, and two Chloromethanes are extracted, and merge organic faciess, and the concentrated post of drying obtains product 56.4mg, yield 77.5%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.8Hz,1H),6.85(d,J=8.9Hz,1H),6.30(d,J= 2.5Hz,1H),5.66(d,J=1.8Hz,1H),4.51(s,1H),4.29–4.22(m,1H),4.06(s,1H),3.79(s, 3H),3.20(s,1H),2.12–2.02(m,1H),1.92–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.60,156.31,153.70,137.85,130.68,122.59, 120.92,114.42,71.09,62.20,55.62,36.43,33.03.
HR-ESI-MS calcd for C15H18NO5[M+H]+292.3071,found292.3078.
Compound 4r-13：Brown solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 54.6mg, yield are 75.1%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.9Hz,2H),6.86(d,J=9.0Hz,2H),6.31(d,J= 2.7Hz,1H),5.67(d,J=1.9Hz,1H),4.52(s,1H),4.30–4.19(m,2H),4.07(s,1H),3.79(s, 3H),3.21(s,1H),2.14–1.99(m,1H),1.97–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.62,156.27,153.70,137.84,130.71,122.57, 120.90,114.39,71.10,62.19,55.60,36.43,32.98.
HR-ESI-MS calcd for C15H18NO5[M+H]+292.3071,found292.3077.
Compound 4s-14：Yellow solid；Under room temperature, compound 3s (35.5mg, 0.25mmol) is different with to n-butylphenyl Cyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, and two Chloromethanes are extracted, and merge organic faciess, and the concentrated post of drying obtains product 60.3mg, yield 76.1%.
1H NMR(500MHz,CDCl3)δ7.26(d,J=1.1Hz,2H),7.12(d,J=8.3Hz,2H),6.31(d,J= 2.6Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.1Hz,1H),4.38–4.20(m,2H),4.07(s,1H), 3.21(s,1H),2.63–2.49(m,2H),2.09–2.04(m,1H),1.95–1.91(m,1H),1.60–1.55(m,2H), 1.37–1.32(m,2H),0.91(t,J=7.3Hz,3H).
13C NMR(125MHz,CDCl3)δ170.58,153.44,137.85,135.17,129.12,122.62, 119.05,71.06,62.20,36.41,35.06,33.77,33.07,22.38,14.05.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3869.
Compound 4r-14：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 63.6mg, yield are 80.2%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.1Hz,2H),7.12(d,J=8.4Hz,2H),6.32(d,J= 2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.4Hz,1H),4.38–4.21(m,2H),4.15–4.02(m, 1H),3.22(s,1H),2.58–2.55(m,2H),2.08–2.04(m,1H),1.94–1.91(m,1H),1.57(ddd,J= 15.3,11.1,7.6Hz,2H),1.34(dd,J=14.9,7.4Hz,2H),0.91(t,J=7.4Hz,3H).
13C NMR(125MHz,CDCl3)δ170.59,153.44,137.85,135.17,129.11,122.62, 119.02,71.06,62.21,36.41,35.06,33.77,33.07,22.38,14.04.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3871.
Compound 4s-15：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and 3,5- 3,5-dimethylphenyls under room temperature Isocyanates (1.2eq) are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, Dichloromethane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 57.8mg, yield 80%.
1H NMR(500MHz,CDCl3)δ7.01(s,1H),6.72(s,1H),6.31(d,J=2.6Hz,1H),5.66(d,J =2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.20(m,1H),4.06(dd,J=9.0,5.7Hz,1H),3.23– 3.20(m,1H),2.28(s,6H),2.08–2.04(m,1H),1.93–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.58,153.33,138.94,137.85,137.46,125.62, 122.56,116.69,71.05,62.18,36.40,33.02,21.46.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3336.
Compound 4r-15：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 61.9mg, yield are 85.7%.
1H NMR(500MHz,CDCl3)δ7.00(s,1H),6.73(s,1H),6.32(d,J=2.7Hz,1H),5.67(d,J =2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.31–4.23(m,1H),4.07(dd,J=9.1,5.6Hz,1H),3.24– 3.20(m,1H),2.29(s,6H),2.09–2.06(m,1H),1.95–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.54,139.03,137.86,137.42,125.72,122.61, 116.67,71.02,62.20,36.41,33.11,21.50.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3335.
Compound 4s-16：Yellow solid；Compound 3s (35.5mg, 0.25mmol) and 3- bromophenyl Carbimide .s under room temperature Ester (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane Alkane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 67.8mg, yield 80%.
1H NMR(500MHz,CDCl3)δ7.65(s,1H),7.28(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,1H), 7.17(dd,J=7.9,2.8Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz, 1H),4.34–4.25(m,2H),4.08(dd,J=9.1,5.5Hz,1H),3.23–3.21(m,1H),2.09–2.05(m,1H), 1.96–1.92(m,1H).
13C NMR(125MHz,CDCl3)δ170.64,153.00,153.00,139.01,137.80,130.52, 126.87,122.94,122.71,121.81,117.32,70.96,62.52,36.38,33.00.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1715.
Compound 4r-16：Yellow solid；Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 69.1mg, yield are 81.5%.
1H NMR(500MHz,CDCl3)δ7.65(s,1H),7.28(d,J=7.6Hz,1H),7.23–7.19(m,1H), 7.16(t,J=7.9Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.4Hz,1H),4.55–4.51(m,1H), 4.32–4.24(m,2H),4.08(dd,J=9.2,5.5Hz,1H),3.25–3.19(m,1H),2.10–2.04(m,1H),1.97– 1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.59,153.00,139.04,137.80,130.51,126.85, 122.92,122.71,121.81,117.36,70.98,62.52,36.39,32.98.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1713.
Embodiment 2：The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 8 benzoic acid replacements
Compound 5s-1～8 universal synthesis method：Compound 3s substituted benzoic acid different from phenyl ring under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows：
Compound 5s-1：White solid；Under room temperature, compound 3s (35.5mg, 0.5mmol) is dissolved in benzoic acid (1.2eq) In dichloromethane, EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloromethane are added Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.6g, and yield is 75.8%.
1H NMR(500MHz,CDCl3)δ8.05(d,J=7.96Hz,2H),7.57(t,J=7.66Hz,1H),7.46(t,J= 7.96,7.66Hz,2H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83, 2.70Hz,2H),4.55(dd,J=9.15,7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.08–3.12(m, 1H),2.07–2.11(m,1H),1.81–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,166.35,138.68,133.00,130.14,129.76, 129.76,128.48,128.48,118.83,70.93,62.95,39.27,31.15.
HR-ESI-MS calcd for C14H14O4Na[M+Na]+269.2483,found269.2473.
Compound 5s-2：White solid；Compound 3s (35.5mg, 0.5mmol) and parabromobenzoic acid (1.2eq) under room temperature It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 69.5g, and yield is 85.8%.
1H NMR(500MHz,CDCl3)δ7.89(d,J=8.46Hz,2H),7.58(d,J=8.46Hz,2H),6.20(d,J= 2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15, 7.80Hz,1H),3.82(dd,J=9.15,4.60Hz,1H),3.06–3.15(m,1H),2.05–2.14(m,1H),1.80– 1.87(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,165.54,138.68,133.16,133.16,131.80, 131.80,129.64,127.90,118.86,70.96,62.93,39.32,31.18.
HR-ESI-MS calcd for C14H14O4Br[M+H]+326.1626,found326.1619.
Compound 5s-3：White solid；Compound 3s (35.5mg, 0.5mmol) and 4-Iodobenzoic acid (1.2eq) under room temperature It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 80.6g, and yield is 86.7%.
1H NMR(500MHz,CDCl3)δ7.78(d,J=8.29Hz,2H),7.59(d,J=8.29Hz,2H),6.20(d,J= 2.85Hz,1H),5.53(d,J=2.85Hz,1H),4.79(td,J=6.83,2.70Hz,2H),4.54(dd,J=9.15, 7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.05–3.12(m,1H),2.04–2.12(m,1H),1.80– 1.86(m,1H)
13C NMR(125MHz,CDCl3)δ170.42,165.79,138.68,136.75,136.75,130.31, 130.31,129.57,118.83,98.61,70.93,62.96,39.29,31.16.
HR-ESI-MS calcd for C14H14O4I[M+H]+373.1630,found373.1626.
Compound 5s-4：White solid；Compound 3s (35.5mg, 0.5mmol) and cumfrey under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 61.6g, and yield is 85.6%.
1H NMR(500MHz,CDCl3)δ7.98(d,J=7.95Hz,2H),7.20(d,J=7.95Hz,2H),6.20(d,J= 2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15, 7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.06–3.11(m,1H),2.93–2.98(m,1H),2.03– 2.09(m,1H),1.82–1.88(m,1H),1.24(s,6H).
13C NMR(125MHz,CDCl3)δ170.42,166.32,152.06,138.68,129.06,129.06, 127.13,125.82,125.82,118.83,70.93,62.96,39.29,34.13,31.16,23.29.
HR-ESI-MS calcd for C17H20O4Na[M+Na]+311.3281,found311.3276.
Compound 5s-5：Yellow solid；Compound 3s (35.5mg, 0.5mmol) and p-tert-butyl benzoic acid under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.7g, and yield is 79.1%.
1H NMR(500MHz,CDCl3)δ7.88(d,J=8.65Hz,2H),7.39(d,J=8.65Hz,2H),7.39(d,J= 8.65Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H), 4.55(dd,J=9.15,7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.08–3.13(m,1H),2.03–2.09 (m,1H),1.80–1.88(m,1H),1.35(s,9H).
13C NMR(125MHz,CDCl3)δ170.42,166.06,158.28,138.68,129.42,127.31, 125.62,118.83,70.93,62.96,39.29,35.26,31.16,30.95.
HR-ESI-MS calcd for C18H22O4Na[M+Na]+325.3546,found325.3556.
Compound 5s-6：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to n-amylbenzene formic acid (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 57.2g, and yield is 72.4%.
1H NMR(500MHz,CDCl3)δ8.03(d,J=8.15Hz,2H),7.22(d,J=8.15Hz,2H),6.21(d,J= 2.85Hz,1H),5.55(d,J=2.85Hz,1H),4.81(td,J=6.83,2.70Hz,2H),4.56(dd,J=9.15, 7.80Hz,1H),3.82(dd,J=9.15,4.60Hz,1H),3.08(m,1H),2.62(t,J=7.40Hz,2H),2.07(m, 1H),1.86(m,1H),1.72(m,2H),1.44(m,2H)1.38(m,2H),0.82(t,J=6.80Hz,3H).
13C NMR(125MHz,CDCl3)δ170.41,166.28,149.07,138.68,129.62,129.62, 129.16,129.16,128.24,118.83,70.93,62.96,39.29,35.36,31.54,31.16,30.75,22.51, 13.98.
HR-ESI-MS calcd for C19H24O4Na[M+Na]+339.3812,found339.3819.
Compound 5s-7：Yellow solid；Compound 3s (35.5mg, 0.5mmol) and p-Methoxybenzoic acid under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 49.5g, and yield is 71.7%.
1HNMR(500MHz,CDCl3)δ7.96(d,J=8.60Hz,2H),6.93(d,J=8.60Hz,2H),6.20(d,J= 2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15, 7.80Hz,1H),3.84(s,3H),3.81(dd,J=9.15,4.60Hz,1H),3.06–3.13(m,1H),2.06–2.12(m, 1H),1.81–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,165.93,165.20,138.68,132.52,123.36, 118.83,115.49,70.93,62.96,56.70,39.29,31.16.
HR-ESI-MS calcd for C15H16O5Na[M+Na]+299.2743,found299.2752.
Compound 5s-8：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to (Trifluoromethyl)benzoic acid. (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 62.8g, and yield is 80%.
1HNMR(500MHz,CDCl3)δ8.10(d,J=8.00Hz,2H),7.86(d,J=8.00Hz,2H),6.19(d,J= 2.85Hz,1H),5.53(d,J=2.85Hz,1H),4.79(td,J=6.83,2.70Hz,2H),4.54(dd,J=9.15, 7.80Hz,1H),3.80(dd,J=9.15,4.60Hz,1H),3.07–3.13(m,1H),2.05–2.11(m,1H),1.80– 1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,165.61,138.67,134.51,131.70,129.87, 125.08,123.60,118.82,70.92,62.94,39.28,31.14.
HR-ESI-MS calcd for C15H14O4F3[M+H]+315.2645,found315.2652.
Embodiment 3：The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 10 cinnamic acid replacements
Compound 6s-1～10 universal synthesis method：Compound 3s substituted cinnamic acid different from phenyl ring under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows：
Compound 6s-1：Yellow solid；Under room temperature, compound 3s (35.5mg, 0.5mmol) is dissolved in cinnamic acid (1.2eq) In dichloromethane, EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloromethane are added Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.2g, yield 67.9%.
1H NMR(500MHz,CDCl3)δ7.78(d,J=15.88Hz,1H),7.47(d,J=7.51Hz,2H),7.42– 7.45(m,3H),6.50(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.10–3.17(m,1H),2.05–2.11(m,1H),1.82–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,144.80,139.18,134.50,130.20, 129.52,129.23,118.83,118.50,71.14,62.75,40.15,31.29.
HR-ESI-MS calcd for C16H17O4[M+H]+273.3038,found273.3052.
Compound 6s-2：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to fluoro cinnamic acid (1.2eq) It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 54.2g, yield 75.2%.
1H NMR(500MHz,CDCl3)δ7.60(d,J=15.88Hz,1H),7.51–7.55(m,2H),7.07–7.10(m, 1H),6.39(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49(dd,J= 9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),3.10–3.18 (m,1H),2.05–2.10(m,1H),1.82–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,169.01,164.50,145.26,139.16,130.46, 130.10,118.81,118.40,116.00,71.13,62.73,40.13,31.27.
HR-ESI-MS calcd for C16H15FO4Na[M+Na]+313.2761,found313.2755.
Compound 6s-3：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to chloro-cinnamic acid (1.2eq) It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 58.6g, yield 76.6%.
1HNMR(500MHz,CDCl3)δ7.65(d,J=15.88Hz,1H),7.40(d,J=8.51Hz,2H),7.35(d,J= 8.51Hz,2H),6.49(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.12–3.16(m,1H),2.03–2.09(m,1H),1.80–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,169.01,142.63,139.18,136.17,133.44, 129.73,128.46,118.82,117.76,71.14,62.75,40.15,31.28.
HR-ESI-MS calcd for C16H15ClO4Na[M+Na]+329.7304,found329.7335.
Compound 6s-4：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to bromo-cinnamic acid (1.2eq) It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 62.0g, yield 70.9%.
1H NMR(500MHz,CDCl3)δ7.63(d,J=15.88Hz,1H)7.53(d,J=8.59Hz,2H),7.45(d,J= 8.59Hz,2H),6.45(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.11–3.16(m,1H),2.04–2.10(m,1H),1.82–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,143.48,139.17,133.74,132.16, 130.06,124.91,118.94,118.83,71.13,62.75,40.14,31.29.
HR-ESI-MS calcd for C16H15BrO4Na[M+Na]+374.1817,found374.1820.
Compound 6s-5：White solid；Compound 3s (35.5mg, 0.5mmol) and p-trifluoromethylcinnamic acid under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 61.4g, yield 72.3%.
1H NMR(500MHz,CDCl3)δ7.70(d,J=15.88Hz,1H),7.65(d,J=8.44Hz,2H),7.60(d,J =8.44Hz,2H),6.42(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.10–3.16(m,1H),2.02–2.09(m,1H),1.81–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,142.91,139.16,137.76,131.70, 128.10,128.10,125.80,125.80,121.25,123.80,118.82,71.12,62.74,40.13,31.28.
HR-ESI-MS calcd for C17H15F3O4Na[M+Na]+363.2836,found363.2817.
Compound 6s-6：Yellow oil；Under room temperature compound 3s (35.5mg, 0.5mmol) with to methyl mercapto cinnamic acid (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.3g, yield 74.6%.
1HNMR(500MHz,CDCl3)δ7.72(d,J=15.88Hz,1H),7.50(d,J=8.50Hz,2H),7.18(d,J= 8.50Hz,2H),6.42(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.10–3.18(m,1H),2.50(s,3H),2.03–2.09(m,1H),1.83–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,145.92,139.18,137.35,133.36, 129.34,126.92,118.83,118.78,71.14,62.75,40.15,31.29,16.00.
HR-ESI-MS calcd for C17H19O4S[M+H]+319.3964,found319.3957.
Compound 6s-7：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to methyl cinnamic acid (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 58.7g, yield 82.1%.
1H NMR(500MHz,CDCl3)δ7.58(d,J=15.88Hz,1H),7.42(d,J=8.07Hz,2H),7.19(d,J =8.07Hz,2H),6.43(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H), 3.10–3.16(m,1H),2.38(s,3H),2.05–2.10(m,1H),1.85–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.02,143.33,141.36,139.19,132.39, 130.33,128.77,118.85,118.37,71.15,62.76,40.16,31.30,22.18.
HR-ESI-MS calcd for C17H19O4[M+H]+287.3304,found287.3321.
Compound 6s-8：White solid；Compound 3s (35.5mg, 0.5mmol) and p-methoxycinnamic acid under room temperature (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.5g, yield 78.8%.
1HNMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.47(d,J=8.51Hz,2H),6.90(d,J= 8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.83(s,3H),3.75(dd,J=9.15, 4.60Hz,1H)3.11–3.16(m,1H),2.02–2.08(m,1H),1.82–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,162.40,145.36,139.18,131.20, 130.21,118.83,117.17,116.00,71.14,62.75,55.60,40.15,31.29.
HR-ESI-MS calcd for C17H19O5[M+H]+303.3298,found303.3279.
Compound 6s-9：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to ethoxy-cinnamic acid (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 58.6g, yield 74.1%.
1H NMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.49(d,J=8.51Hz,2H),6.98(d,J =8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),4.09(q,J=6.96Hz,2H),3.75(dd,J =9.15,4.60Hz,1H),3.12–3.17(m,1H),2.04–2.09(m,1H),1.83–1.89(m,1H),1.42(t,J= 6.96Hz,3H).
13C NMR(125MHz,CDCl3)δ170.43,169.02,158.86,145.23,139.19,129.89, 127.67,118.84,117.18,115.00,71.15,64.46,62.76,40.16,31.28,14.75.
HR-ESI-MS calcd for C18H21O5[M+H]+317.3563,found317.3577.
Compound 6s-10：White solid；Under room temperature compound 3s (35.5mg, 0.5mmol) with to propoxyl group cinnamic acid (1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 62.6g, yield 75.9%.
1H NMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.47(d,J=8.51Hz,2H),6.97(d,J =8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49 (dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.95(t,J=7.11Hz,2H),3.75(dd,J =9.15,4.60Hz,1H),3.11–3.17(m,1H),2.05–2.10(m,1H),1.85–1.89(m,1H),1.79–1.83(m, 2H),1.04(t,J=7.36Hz,3H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,159.74,145.23,139.18,129.90, 127.45,118.83,117.17,114.89,71.14,69.10,62.75,40.15,31.29,22.20,10.40.
HR-ESI-MS calcd for C19H23O5[M+H]+331.3829,found331.3836.
Embodiment 4：Compound 4r-1～16,4s-1～16,5s-1～8,6s-1～10 suppress LPS induction RAW264.7's NO generates activity
（1）Sample is configured
4r-1～16,4s-1～16,5s-1～8,6s-1～10, the southern regions of the Yunnan Province ocean ear chrysanthemum lactone A and the positive prepared by embodiment 1 Comparison medicine aminoguanidine（Sigma-Aldrich, purity>98.0%）Use DMSO（Dimethyl sulfoxide）(Merck), after dissolving, add PBS (-)（Phosphate buffer）The solution of 10mM is made into, the sample of 0,0.1,0.5,5,20 μM of gradient concentration is further diluted to.With The LPS (Lipopolysaccharides, lipopolysaccharide, sigma, Cat.L-2880) of 10 μ g/mL is derivant.
（2）Experimental technique
Mouse macrophage RAW264.7（It is purchased from Shanghai Sheng Ke institutes cell resource center）At 37 DEG C, 5%CO2In incubator Cellar culture is in DMEM culture fluid.By 1 μ L/mL LPS during experiment（Lipopolysaccharide）(being dissolved in distilled water) adds 100mL concentration For 2 × 106In the cell suspension of μ g/mL, between the content after 18h with Griess methods by measure cell supernatant nitrite It is reversed to reflect NO growing amounts：100mL cell culture fluids are taken, equivalent Griess is added（Ge Lisi）Reagent, determines light absorption value.
（3）Evaluation criterion and statistical method
Trap is surveyed at 570nm wavelength, with NaNO2Standard solution draws standard curve, calculates the concentration of nitrite. Each group experimental result carries out statistical analysiss in SPSS software one-way ANNOVA methods.
（4）Experimental result
Test result indicate that 4r-1～16,4s-1～16,5s-1～8 and 6s-1～10 pair LPS induction RAW264.7 macrophages The NO of cell is generated obvious inhibitory activity（The results are shown in Table 1）, illustrate which has anti-inflammatory activity.
Table 1：4r-1～16,4s-1～16,5s-1～8,6s-1～10 suppress the NO of LPS induction RAW264.7 to generate activity
Embodiment 5：Compound 4r-1～16,4s-1～16,5s-1～8, the cytotoxicity of 6s-1～10
（1）Sample is configured
4r-1～16 of the preparation of embodiment 1,4s-1～16,5s-1～8,6s-1～10 DMSO（Dimethyl sulfoxide） (Merck), after dissolving, add PBS (-)（Phosphate buffer）It is made into the solution of 10mM
（2）Experimental technique
Mouse macrophage RAW264.7（It is purchased from Shanghai Sheng Ke institutes cell resource center）At 37 DEG C, 5%CO2In incubator Cellar culture is in DMEM culture fluid.Take the logarithm during experiment trophophase RAW264.7 cells it is resuspended Jing after trypsinization, Obtain 1 × 105The cell suspension of/ml.It is plated in 96 orifice plates, continues culture 18 hours.It is further cultured for after dosing 18 hours, per hole 10 Μ l MTT solution (5mg/ml) are added, continues culture 3 hours.
（3）Evaluation criterion and statistical method
Trap is surveyed at 570nm wavelength, each group experimental result is counted in SPSS software one-wayANNOVA methods Analysis.
（4）Experimental result
Experimental result finds that all toxicity of compound are all relatively low, toxicity IC5020 μM are all higher than, and in the ear chrysanthemum of relative the southern regions of the Yunnan Province ocean Ester A toxicity is lower.
Below the preferred embodiment to the invention is illustrated, but the invention be not limited to it is described Embodiment, those of ordinary skill in the art can also make a variety of equivalents on the premise of without prejudice to the invention spirit Modification or replacement, the modification of these equivalents or replacement are all contained in the application claim limited range.

Claims (5)

1. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates, benzoic acid or cinnamic acid replace, its chemical constitution such as formula 1, Shown in formula 2 or formula 3：
In formula 1, R1 is respectively：
In formula 2, R2 is respectively：
In formula 3, R3 is respectively：
2. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates as claimed in claim 1, benzoic acid or cinnamic acid replace Preparation method, it is characterised in that the synthetic route of the preparation method is：
Reactions steps are as follows：
Dicyclohexylcarbodiimide and ether is dissolved in dimethylamino naphthyridine, under the conditions of subzero 30 DEG C, is added dropwise over acetylenecarboxylic acid, suitable The diethyl ether solution of butylene glycol；After completion of dropping, room temperature reaction obtains compound 1 in 12 hours；In catalyst 1,5- cyclo-octadiene chlorine Under the effect of rhodium dimerization, silver hexafluoroantimonate and chiral ligand dinaphthalene diphenyl phosphine, compound 1 can change into two kinds of configurations of R, S respectively Compound 2r and 2s；, by borane reduction into compound 3r and 3s, compound 3r and 3s is different from phenyl ring for compound 2r and 2s Substituted isocyanates, benzoic acid, Cortex Cinnamomi acid reaction can obtain target compound 4r, 4s, 5s, 6s.
3. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates as claimed in claim 1, benzoic acid or cinnamic acid replace Application in anti-inflammatory drug is prepared.
4. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates according to claim 3, benzoic acid or cinnamic acid replace exists Prepare the application in anti-inflammatory drug, it is characterised in that described anti-inflammatory drug is to be replaced by isocyanates, benzoic acid or cinnamic acid The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue as active component and pharmaceutical composition made by conventional pharmaceutical carrier.
5. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates according to claim 4, benzoic acid or cinnamic acid replace exists Prepare the application in anti-inflammatory drug, it is characterised in that described pharmaceutical composition is tablet, capsule, drop pill, granule, note Penetrate agent or aerosol.
CN201410098808.8A 2014-03-18 2014-03-18 The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace Active CN104926761B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410098808.8A CN104926761B (en) 2014-03-18 2014-03-18 The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410098808.8A CN104926761B (en) 2014-03-18 2014-03-18 The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace

Publications (2)

Publication Number Publication Date
CN104926761A CN104926761A (en) 2015-09-23
CN104926761B true CN104926761B (en) 2017-03-29

Family

ID=54114216

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410098808.8A Active CN104926761B (en) 2014-03-18 2014-03-18 The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace

Country Status (1)

Country Link
CN (1) CN104926761B (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5905089A (en) * 1997-04-14 1999-05-18 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Use of sesquiterpene lactones for treatment of severe inflammatory disorders
WO2003057686A1 (en) * 2002-01-07 2003-07-17 E.I. Du Pont De Nemours And Company Alpha-methylenelactone synthesis in supercritical fluids
US20070073067A1 (en) * 2005-08-25 2007-03-29 Hutchenson Keith W Supercritical fluid phase synthesis of methylene lactones using catalysts derived from hydrotalcites
CN102274210A (en) * 2011-06-17 2011-12-14 河北医科大学 Applications of ineupatorolide B in preparation of antitumor drugs
CN102731464A (en) * 2011-04-12 2012-10-17 沈阳药科大学 Sesquiterpene lactone compound, its preparation methods and application
CN103088083A (en) * 2013-02-19 2013-05-08 齐齐哈尔大学 Method for preparing anti-inflammation and anti-tumor activity sesquiterpene lactone compounds
CN103102336A (en) * 2013-01-15 2013-05-15 上海交通大学 Inula wissmannian extract and preparation thereof and application in preparation of antitumor drug

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5905089A (en) * 1997-04-14 1999-05-18 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Use of sesquiterpene lactones for treatment of severe inflammatory disorders
WO2003057686A1 (en) * 2002-01-07 2003-07-17 E.I. Du Pont De Nemours And Company Alpha-methylenelactone synthesis in supercritical fluids
US20070073067A1 (en) * 2005-08-25 2007-03-29 Hutchenson Keith W Supercritical fluid phase synthesis of methylene lactones using catalysts derived from hydrotalcites
CN102731464A (en) * 2011-04-12 2012-10-17 沈阳药科大学 Sesquiterpene lactone compound, its preparation methods and application
CN102274210A (en) * 2011-06-17 2011-12-14 河北医科大学 Applications of ineupatorolide B in preparation of antitumor drugs
CN103102336A (en) * 2013-01-15 2013-05-15 上海交通大学 Inula wissmannian extract and preparation thereof and application in preparation of antitumor drug
CN103088083A (en) * 2013-02-19 2013-05-08 齐齐哈尔大学 Method for preparing anti-inflammation and anti-tumor activity sesquiterpene lactone compounds

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Catalytic Asymmetric Synthesis of (+)-Anthecotulide Using Enyne and Meyer-Schuster Rearrangements;David M.Hodgson et al;《Organic Letters》;20110710;第13卷(第21期);第5751-5753页 *
HPLC法同时测定旋覆花属植物中5种倍半萜内酯成分的含量;杨茜 等;《沈阳药科大学学报》;20120229;第29卷(第2期);第116-120页 *
Synthesis and evaluation of new a-methylene-r-lactone carbamates with NO production inhibitory effects in lipopolysaccharide-induced RAW264.7 macrophages;Wen-Hao Shao et al;《European Journal of Medicinal Chemistry》;20150214;第93卷;第274-280页 *
Winolides A–C,bioactive sesquiterpene lactones with unusual 5,6-secoeudesmane frameworks from Inula wissmanniana;Xiang-Rong Cheng et al;《RSC Advances》;20140721;第4卷;第33815-33818页 *
四种旋覆花属植物的化学成分及生物活性研究;成向荣;《中国博士学位论文全文数据库 医药卫生科技辑》;20121215;第E057-9页 *
滇南洋耳菊内酯A的合成、构型确定及其衍生物的活性研究;邵文浩;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20150415;第E057-60页 *

Also Published As

Publication number Publication date
CN104926761A (en) 2015-09-23

Similar Documents

Publication Publication Date Title
Pieters et al. Synthesis and biological evaluation of dihydrobenzofuran lignans and related compounds as potential antitumor agents that inhibit tubulin polymerization
Paranagama et al. Heptaketides from Corynespora sp. inhabiting the cavern beard lichen, Usnea cavernosa: first report of metabolites of an endolichenic fungus
Olmedo et al. 3-Phenylcoumarins as inhibitors of HIV-1 replication
Jada et al. * Semisynthesis and cytotoxic activities of andrographolide analogues
Zhao et al. Virosaines A and B, two new birdcage-shaped Securinega alkaloids with an unprecedented skeleton from Flueggea virosa
CN101497593B (en) 5-hydroxy coumarin and pyranoid type coumarin compounds, synthesizing method and use
Bagal et al. Dimerization of butenolide structures. A biomimetic approach to the dimeric sesquiterpene lactones (±)-biatractylolide and (±)-biepiasterolide
An et al. Spirotrichilins A and B: two rearranged spirocyclic limonoids from Trichilia connaroides
JP2006290871A (en) Compound exhibiting anti-cancer property, intermediate therefor and method for producing the same
Tai et al. New pyrano-pyrone from Goniothalamus tamirensis enhances the proliferation and differentiation of osteoblastic MC3T3-E1 cells
Tamura et al. Bioisostere of valtrate, anti-HIV principle by inhibition for nuclear export of Rev
Zhang et al. Chuktabrins A and B, two novel limonoids from the twigs and leaves of Chukrasia tabularis
CN106365986A (en) Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam
Fernández-Mateos et al. Synthesis of the BCDE molecular fragment of azadiradione mediated by titanocene (III)
Koca et al. Multicomponent Reactions of Furan‐2, 3‐diones: Synthesis and Characterizations of Furo [3, 2‐c] pyran‐4‐ones
CN104926761B (en) The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace
CN104817472B (en) A kind of novel gossypol derivative and preparation method thereof and antitumor are applied
Caprioglio et al. Biomimetic approaches to the synthesis of natural disesquiterpenoids: An update
Wzorek et al. Synthesis, characterization and antiproliferative activity of β-aryl-δ-iodo-γ-lactones
Mahadeo et al. Antiplasmodial diterpenoids from Psiadia arguta
CN103159776B (en) The total synthesis method of a kind of natural active product hypoxylonin and analogue thereof
Basak et al. Applications of [4+ 2] anionic annulation and carbonyl-ene reaction in the synthesis of anthraquinones, tetrahydroanthraquinones, and pyranonaphthoquinones
Sass et al. Selectivity in reduction of natural furanoheliangolides with Stryker's reagent
CN103254187B (en) A kind of preparation method of Taxane derivative
CN101792478A (en) Light affinity labelling small molecular probe based on maslinic acid and preparation method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant