CN106565734B - A kind of psoralen ester derivative and purposes - Google Patents
A kind of psoralen ester derivative and purposes Download PDFInfo
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- CN106565734B CN106565734B CN201610983128.3A CN201610983128A CN106565734B CN 106565734 B CN106565734 B CN 106565734B CN 201610983128 A CN201610983128 A CN 201610983128A CN 106565734 B CN106565734 B CN 106565734B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of psoralen ester derivative and purposes, such compound is 4 methyl, 7 Hydroxycoumarin（Intermediate 1）；4 methyl, 7 hydroxy ethoxy cumarin（Intermediate 2）；4 methyl, 7 formyl methoxy coumarin（Intermediate 3）；5 methyl 7HFurans [3,2g] 7 ketone (compound 4) of chromene；7 oxos 7HFurans [3,2g] 5 formaldehyde of chromene（Compound 5）；5 methylols 7HFurans [3,2g] 7 ketone of chromene（Compound 6）；(7 oxos 7HFurans [3,2g] 5 base of chromene) methyl acetic acid ester（Compound 7）With compound 8a 8p.And investigate influence of this 20 psoralen ester derivatives to melanogenesis in mouse B16 cells and to Candida albicans, Escherichia coli, staphylococcus aureus inhibiting effect.Its result compound 47, compound 8a 8d and compound 8k 8o are used to prepare the drug for the treatment of leucoderma.The psoralen Schiff bases derivative obtained is used to prepare the drug for the treatment of candida albicans infection, and compound 5 and compound 7 are additionally operable to prepare the drug for the treatment of infection of staphylococcus aureus.
Description
Technical field
The present invention relates to a kind of psoralen ester derivatives and purposes more particularly to such compound to pass through anti-leucoderma
And Antimicrobial Screening, all psoralen ester derivatives are used equally for clinically preparing treatment Candida albicans (Candida
Albicans) the drug of infection；Remaining 13 compound in addition to 8e-8j, 8p are used equally for clinically preparing treatment leucoderma
The drug of wind；And compound 5 and 7 can also be used to clinically prepare treatment staphylococcus aureus (Staphylococcus
Aureus) the drug of infection.
Background technology
Leucoderma is a kind of common spontaneous or idiopathic depigmentation dermatoses, and it is big to be referred to as world's skin disease three
One of chronic disease perplexs the patient in more than 50,000,000 whole world.In the world, different geographical, not agnate intercurrent disease rate are from 0.1%-
8% differs, and China's population illness rate is 0.56% or so, and approximately half of patient fell ill before 20 one full year of life, male and female
The illness rate of property is equal.Leucoderma is mainly shown as skin, the hickie of mucous membrane and ash/white hair etc..Doctor trained in Western medicine thinks leucoderma
It is caused by the hypofunction, forfeiture of tyrosinase system in the melanocyte of skin and hair follicle.
Psoralea corylifolia is the drying and ripening fruit of pulse family annual herb plant psoralea corylifolia (Psoralea corylifolia L.)
It is real, record in《Chinese Pharmacopoeia》、《Uygur medicine will》、《Chinese book on Chinese herbal medicine-Uygur's bundling》Deng, be the successive dynasties tradition Uygur cure
Treat the main classical drug of leucoderma.Uygur's medicine thinks that leucoderma is mainly caused by abnormal phlegm, advocates during treatment clear
Except abnormal humour, abnormal makings is corrected, so as to restore body natural force.Psoralea corylifolia have raw dry heat, remove abnormal lymphatic temperament,
Net blood removing toxic substances increases pigment, kills anthelmintic and other effects.In addition, psoralea corylifolia also has antibacterial, estrogen-like action, antitumor, anti-
The multiple biological activities such as oxidation, immunological regulation and antidepression.
At present with plant psoralea corylifolia drug as main component and preparation, clinically it is mainly used for treating leucoderma：As again
Square psoralea corylifolia particle, compound psorolea tincture, drives white Ba Busi pieces, compound kaliziranding (dimension medicine name Wei A at malaytea scurfpea injection
Dew) etc..Although tieing up medicine treatment leucoderma significant effect, with the obvious advantage, the research of its material base is weak, mechanism of action and body
Inside and outside metabolic process is not also apparent, serious to constrain its secondary development.
By studying for many years, domestic and international researcher divides from psoralea corylifolia (Psoralea corylifolia L.)
Separate out Psoralens resistance compound (furocoumarin compound), flavonoids, terpene and a small amount of lipid and volatile oil.Its
Middle Psoralens resistance compound (furocoumarin compound) is used as main chemical compositions therein, and research range is most wide.
Psoralens resistance compound (Psoralen) is the current most common photosensitizer of clinical treatment leucoderma, but
It is that must coordinate daylight or long wave ultraviolet (UVA) irradiation treatment, so such therapy is known as PUVA (Psoralen+
UVA).Common have a 8-methoxypsoralen (8-MOP) and 5-bergapten (5-MOP), later and artificial synthesized
Trimethyl psoralen (TMP), as shown in structure.In the treatment of leucoderma, PUVA can activate tyrosinase activity, catalysis
Melanin genesis promotes the division and movement of melanocyte, finally increases B16 cell, and hickie color is gradually restored.
The structure of three kinds of common Psoralens resistance compounds
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The present invention at home and abroad in relation to patent, the comprehensive analysis of document and this seminar previous research work on the basis of,
Reactive compound-psoralen in the plant is further transformed and is modified, by esterification by substituted-phenyl
Etc. being introduced into psoralen molecules, its druggability is improved, and have studied these ester derivatives to melanocyte in mouse B16 cells
The influence of generation, to find significant in efficacy, target spot clearly, the mechanism of action clearly anti-leucoderma new drug；In addition to this, it also grinds
These derivatives have been studied carefully to Candida albicans (Candida albicans), Escherichia coli (Escherichia coli), golden yellow
The inhibiting effect of color staphylococcus (Staphylococcus aureus), to find the drug candidate with antibacterial activity.
Invention content
The object of the present invention is to provide a kind of psoralen ester derivative and purposes, such compound for 4- methyl-
Umbelliferone (intermediate 1)；4- methyl -7- hydroxy ethoxies cumarins (intermediate 2)；4- methyl -7- formyl methoxy basic notes
Legumin (intermediate 3)；5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)；7- oxo -7H- furans [3,2-
G] chromene -5- formaldehyde (compound 5)；5- methylol -7H- furans [3,2-g] chromene -7- ketone (compound 6)；(7-
Oxo -7H- furans [3,2-g] chromene -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.And investigate this 20
Influence of a psoralen ester derivative to melanogenesis in mouse B16 cells and to Candida albicans, Escherichia coli, golden yellow
The staphylococcic inhibiting effect of color, anti-leucoderma result：Remaining 13 compound in addition to 8e-8j, 8p are preparing treatment in vain
The medicinal usage of purplish or white patches on the skin wind.The anti-bacterial result：The 20 psoralen ester derivatives obtained are preparing treatment Candida albicans sense
The medicinal usage of dye, and compound 5 and 7 can be additionally used in the medicinal usage for preparing treatment infection of staphylococcus aureus.
A kind of psoralen ester derivative of the present invention, such derivant structure formula are：
Wherein：Compound 4 is 5- methyl -7H- furans [3,2-g] chromene -7- ketone；
Compound 5 is 7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde；
Compound 6 is 5- methylol -7H- furans [3,2-g] chromene -7- ketone；
Compound 7 is (7- oxo -7H- furans [3,2-g] chromene -5- bases) methyl acetic acid ester；
Compound 8a is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methyl) benzoic ether；
Compound 8b is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methyl) benzoic ether；
Compound 8c is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methoxyl groups) benzoic ether；
Compound 8d is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methoxyl groups) benzoic ether；
Compound 8e is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- chlorine) benzoic ether；
Compound 8f is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- chlorine) benzoic ether；
Compound 8g is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,4- dichloros) benzoic ether；
Compound 8h is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dichloros) benzoic ether；
Compound 8i is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- fluorine) benzoic ether；
Compound 8j is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2,4- difluoros) benzoic ether；
Compound 8k is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl benzoic acid ester；
Compound 8l is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- nitros) benzoic ether；
Compound 8m is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- trifluoromethyls) benzoic acid
Ester；
Compound 8n is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3- nitros) benzoic ether；
Compound 8o is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dinitros) benzoic acid
Ester；
Compound 8p is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- iodine) benzoic ether.
Purposes of the psoralen ester derivative in the drug for preparing treatment candida albicans infection.
Compound 4-7, compound 8a-8d and compound 8k-8o are controlled in preparation in the psoralen ester derivative
Treat the purposes in the drug of leucoderma.
Compound 5 and 7 is in the medicine for preparing treatment infection of staphylococcus aureus in the psoralen ester derivative
Purposes in object.
A kind of psoralen ester derivative of the present invention and purposes, such compound are former by starting of resorcinol
Material, under the action of sulfuric acid, is condensed to yield 4-methyl-7-hydroxycoumarin (intermediate 1) with ethyl acetoacetate first；It is intermediate
4- methyl -7- hydroxy ethoxies cumarins (intermediate 2) are obtained by the reaction in body 1 with chlorethanol again；Then the oxidation of intermediate 2 is obtained into 4-
Methyl -7- formyls methoxy coumarin (intermediate 3)；By intermediate 3 under the catalysis of sodium hydroxide, cyclization forms furan nucleus,
So as to obtain 5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)；After obtained parent nucleus compound 4, into
One step aoxidizes its 5- methyl using selenium dioxide, obtains 7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde (chemical combination
Object 5)；Again at ambient temperature, the aldehyde radical of compound 5 is reduced into methylol, obtains 5- methylol -7H- furans [3,2-g] benzene
And pyrans -7- ketone (compound 6)；Finally, use acetic anhydride and different substituted benzoic acids that (7- is prepared for esterifying reagent
Oxo -7H- furans [3,2-g] chromene -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.Again by acquisition
Influence of this 20 psoralen ester derivatives to melanogenesis in mouse B16 cells and to Candida albicans, Escherichia coli,
The inhibiting effect of staphylococcus aureus is investigated, result：
Anti- leucoderma result is shown：Compared with negative control, remaining 13 compound in addition to 8e-8j, 8p can promote
The generation of melanocyte in B16 cells, and facilitation is differed from 112% to 200%；Compared with positive control, compound 6,8a-
8d, 8l, 8n-8o are superior to the facilitation of melanogenesis positive control, and wherein compound 8n and 8o is to the rush of melanogenesis
Into effect close to 1.5 times of positive control.
The anti-bacterial result is shown：The 20 psoralen ester derivatives obtained are to Candida albicans (Candida
Albicans) there is inhibiting effect, wherein compound 5 is to Escherichia coli (Escherichia coli) and staphylococcus aureus
(Staphylococcus aureus) also shows inhibiting effect, and to Candida albicans (Candida albicans)
Activity is better than positive control amphotericin B (Amphotericin B)；Compound 7 is to staphylococcus aureus
(Staphylococcus aureus) also shows inhibiting effect, and to Candida albicans (Candida albicans)
Activity is better than positive control amphotericin B (Amphotericin B).All compounds are used equally for clinically preparing treatment in vain
The drug of color candida albicans (Candida albicans) infection, and compound 5 and compound 7 can also be used to clinically prepare treatment
The drug of staphylococcus aureus (Staphylococcus aureus) infection.
A kind of psoralen ester derivative of the present invention, structure is as shown in logical formula (I)：
The preparation method of psoralen ester derivative of the present invention follows these steps to carry out：
The preparation of intermediate 1：
A, under condition of ice bath, resorcinol is dissolved in suitable dry Isosorbide-5-Nitrae-dioxane, is stirred to all molten
Solution, is slowly added dropwise the concentrated sulfuric acid, its temperature is made to be no more than 20 DEG C, after being added dropwise, ethyl acetoacetate is added, then heats to
60 DEG C, being sufficiently stirred makes it the reaction was complete, and reaction solution is poured into ice water, is adopted and is extracted with ethyl acetate after standing, organic to be harmonious
And it is dry, intermediate Isosorbide-5-Nitrae-Methyl-7-hydroxy-coumarin is obtained after concentration；
The preparation of intermediate 2：
B, appropriate potassium carbonate and 4-methyl-7-hydroxycoumarin are dissolved in the acetone of 20mL, and add in ethylene chlorhydrin,
Back flow reaction all disappears to raw material, and reaction solution filtering, concentration, by residue using column chromatography gradient elution, eluant, eluent is volume
Petroleum ether than 1: 1: ethyl acetate is to get intermediate 2,4- methyl -7- hydroxy ethoxy cumarins；
The preparation of intermediate 3：
C, by oxalyl chloride as dimethyl sulfoxide (DMSO) (DMSO) in -78 DEG C of low-temp reaction device, is slowly added dropwise, stirring half is small
When, then the obtained 4- methyl -7- ethoxys oxygroup cumarins of step b are dissolved in dry dichloromethane, it is slowly added dropwise
It into reaction system, stirs half an hour, then it is complex dissociation formed in reaction system that triethylamine, which is added dropwise, drips after being added dropwise
Room temperature is slowly extended to after adding, reaction solution is washed three times, and organic phase is dried overnight, and is concentrated to give intermediate 3,4- methyl 7- formyls
Methoxy coumarin；
The preparation of compound 4：
D, the NaOH aqueous solutions of 1mol/L are prepared, heating makes its reflux, by 4- methyl -7- formyls obtained in step c
Methoxy coumarin is dissolved in 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of reflux, is sufficiently stirred and keeps
Back flow reaction all disappears to raw material, is cooled to room temperature, and adds in 1mol/L hydrochloric acid solutions and adjusts pH to neutrality, ethyl acetate extraction
It takes, merges organic phase, concentration, by residue using column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 7: 1: acetic acid second
Ester is to get compound 4,5- methyl -7H- furans [3,2-g] chromene -7- ketone；
The preparation of compound 5：
E, the obtained compounds 4 of step d and selenium dioxide are dissolved in dry dimethylbenzene, are heated to back flow reaction,
It after raw material all disappears, is cooled to room temperature, mother liquor filtering, concentration, by residue using column chromatography gradient elution, eluant, eluent is body
Product ratio 10:1 petroleum ether: ethyl acetate is to get compound 5,7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde；
The preparation of compound 6：
F, compound 5 obtained in step e is dissolved in absolute ethyl alcohol, being sufficiently stirred makes its dissolving, adds in by several times
Sodium borohydride, continuation are reacted at room temperature until raw material all disappears, and reaction is quenched in addition dilute hydrochloric acid, and acetic acid is used after being diluted with water
Ethyl ester extracts, organic phase drying, concentration, and by residue using column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 5: 1:
Ethyl acetate is to get compound 6,5- methylol -7H- furans [3,2-g] chromene -7- ketone；
The preparation of compound 7：
G, compound 6 acquired in step f, 4- dimethylamino pyridines and a drop acetic anhydride are dissolved in pyrrole dry on a small quantity
It in pyridine, is stirred overnight at room temperature, adds in appropriate ice water, ethyl acetate extraction, organic phase drying, concentration, by residue using column chromatography
Gradient elution, eluant, eluent are the petroleum ether of volume ratio 10: 1: ethyl acetate is to get compound 7, (7- oxo -7H- furans [3,2-
G] chromene -5- bases) methyl acetic acid ester；
The preparation of compound 8a-8p：
H, under condition of ice bath, by compound 7 obtained in step g, dicyclohexylcarbodiimide (DCC), 4- dimethylamine
Yl pyridines (DMAP) and corresponding benzoic acid are dissolved in suitable dichloromethane, and being sufficiently stirred makes it complete molten, moves to room temperature condition
Lower the reaction was continued, and after raw material all disappears, filtering, mother liquor is washed successively with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution,
Dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is volume ratio 15: 1-10:1 petroleum ether: ethyl acetate,
Up to compound 8a-8p；
Psoralen ester derivative of the present invention and purposes, wherein psoralen ester derivative, are with isophthalic
Diphenol is starting material, obtains 4- methylumbelliferones (intermediate 1) with ethyl acetoacetate under the action of sulfuric acid；In
4- methyl -7- hydroxy ethoxies cumarins (intermediate 2) are obtained by the reaction in mesosome 1 with chlorethanol again；The ethoxy of oxidation intermediates 2 obtains
To 4- methyl -7- formyls methoxy coumarins (intermediate 3)；Cyclization obtains 5- methyl -7H- to intermediate 3 in the presence of alkali again
Furans [3,2-g] chromene -7- ketone (compound 4).Next, further oxidation 4 obtains 7- oxo -7H- furans [3,2-g]
Chromene -5- formaldehyde (compound 5)；5 aldehyde radical is reduced into methylol again, obtains 5- methylol -7H- furans [3,2-g]
Chromene -7- ketone (compound 6)；Finally, 6 are esterified using acetic anhydride and different substituted benzoic acids, (7- oxygen is prepared
Generation -7H- furans [3,2-g] chromene -5- bases) methyl acetic acid ester (compound 7) and compound 8a-8p.Chemical equation is：
(i) ethyl acetoacetate, the concentrated sulfuric acid, temperature 60 C；(ii) chlorethanol, potassium carbonate, acetone, reflux；(iii) it is warm
- 78 DEG C of degree, oxalyl chloride, dimethyl sulfoxide (DMSO), triethylamine, dichloromethane；(iv) 1M sodium hydrate aqueous solutions, Isosorbide-5-Nitrae-dioxane；
(v) selenium dioxide, dimethylbenzene, reflux；(vi) absolute ethyl alcohol, sodium borohydride, room temperature；(vii) 4- dimethylamino pyridines, acetic acid
Acid anhydride, pyridine, room temperature；(viii) dicyclohexylcarbodiimide, 4- dimethylamino pyridines, dichloromethane, 0 DEG C-room temperature of temperature；Wherein
R1Respectively 4- methyl, 2- methyl, 4- methoxyl groups, 2- methoxyl groups, 4- chlorine, 2- chlorine, 3,4- dichloros, 3,5- dichloros, 4- fluorine, 2,4-
Difluoro, hydrogen, 4- nitros, 4- trifluoromethyls, 3- nitros base, 3,4- dinitros, 2- iodine.
Specific embodiment
According to embodiment, the present invention is further described, but the present invention is not limited only to these embodiments；
Reagent：All reagents are that commercially available analysis is pure；
Embodiment 1
The preparation of intermediate 2：
At ambient temperature, 1.76g (10mmol) intermediate 1 and 2.76g (20mmol) potassium carbonate are dissolved in 50mL third
In ketone, 1.20g (15mmol) ethylene chlorhydrin is added, is heated to back flow reaction, after raw material all disappears, stop reaction, it is cold
But to room temperature, filtering, filtrate concentration, by residue using column chromatography gradient elution, eluant, eluent is the petroleum ether of volume ratio 1: 1: second
Acetoacetic ester is to get 2.10g intermediates 2,4- methyl -7- hydroxy ethoxy cumarins；
The nuclear magnetic data of 4- methyl -7- hydroxy ethoxies cumarins (intermediate 2)：
1H NMR(400MHz,CDCl3) d 7.51 (d, J=9.0Hz, 1H), 6.91-6.83 (m, 2H), 6.15 (d, J=
1.1Hz, 1H), 4.15 (t, J=8.7Hz, 2H), 4.01 (m, 2H), 2.40 (d, J=1.1Hz, 3H)
The preparation of intermediate 3：
Under the conditions of the low-temp reaction of -78 DEG C of temperature, 50.25g (2mmol) oxalyl chloride is dissolved in a small amount of drying dichloromethane
In alkane, the dichloromethane solution containing 0.16g (2mmol) dimethyl sulfoxide (DMSO) (DMSO) is slowly added dropwise, stirs half an hour, then will
0.22g (1mmol) intermediate 2 is dissolved in dry dichloromethane, is slowly added dropwise into reaction system, is stirred after being added dropwise
0.51g (5mmol) triethylamine is finally added dropwise to reaction system, makes complex dissociation formed in reaction system by half an hour, drop
Room temperature is slowly extended to after adding, reaction solution is washed three times, and organic phase is dried overnight, and is concentrated to give 0.21g intermediates 3,4- first
Base 7- formyl methoxy coumarins；
The nuclear magnetic data of 4- methyl 7- formyls methoxy coumarins (intermediate 3)：
1H NMR(400MHz,CDCl3) δ 9.85 (s, 1H), 7.53 (d, J=8.8Hz, 1H), 6.89 (dd, J=8.8,
2.6Hz, 1H), 6.78 (d, J=2.5Hz, 1H), 6.15 (d, J=1.0Hz, 1H), 4.68 (s, 2H), 2.39 (d, J=0.9Hz,
3H).
The preparation of compound 4：
The sodium hydrate aqueous solution of 1M is configured, heating makes its reflux, by 1.09g (5mmol) 4- methyl -7- formyl methoxyl groups
Cumarin is dissolved in 50mL 1-, in 4 dioxane, is slowly added dropwise into the NaOH aqueous solutions of the 1mol/L of reflux, is sufficiently stirred
It all disappears, is cooled to room temperature to raw material, add in 1mol/L hydrochloric acid solutions and adjust pH to neutrality, ethyl acetate extraction is associated with
Machine phase, concentration, petroleum ether of the eluant, eluent for volume ratio 7: 1 is used by residue:Ethyl acetate column chromatography gradient elution to get
0.60g compounds 4,5- methyl -7H- furans [3,2-g] chromene -7- ketone；
The nuclear magnetic data of 5- methyl -7H- furans [3,2-g] chromene -7- ketone (compound 4)：
1H NMR(400MHz,CDCl3) δ 7.81 (s, 1H), 7.69 (d, J=2.2Hz, 1H), 7.47 (s, 1H), 6.85 (d,
J=2.1Hz, 1H), 6.27 (s, 1H), 2.50 (s, 3H)
The preparation of compound 5：
0.20g (1mmol) compound 4 and 0.17g (1.5mmol) selenium dioxide are dissolved in dry dimethylbenzene, heated
It to back flow reaction, after raw material all disappears, is cooled to room temperature, mother liquor filtering, concentration washes residue using column chromatography gradient
De-, eluant, eluent is volume ratio 10:1 petroleum ether: ethyl acetate is to get 0.16g compounds 5,7- oxo -7H- furans [3,2-g]
Chromene -5- formaldehyde；
The nuclear magnetic data of 7- oxo -7H- furans [3,2-g] chromene -5- formaldehyde (compound 5)：
1H NMR(400MHz,CDCl3) δ 10.14 (s, 1H), 8.90 (s, 1H), 7.72 (d, J=2.1Hz, 1H), 7.54
(s, 1H), 6.89 (d, J=2.0Hz, 1H), 6.86 (s, 1H)
The preparation of compound 6：
0.21g (1mmol) compound 5 is dissolved in absolute ethyl alcohol, being sufficiently stirred makes its dissolving, adds in 0.019g by several times
(0.5mmol) sodium borohydride, continuation are reacted at room temperature until raw material all disappears, and reaction is quenched in addition dilute hydrochloric acid, adds water dilute
It is extracted with ethyl acetate after releasing, organic phase drying, concentration, by residue using column chromatography gradient elution, eluant, eluent is volume ratio 5: 1
Petroleum ether: ethyl acetate is to get 0.17g compounds 6,5- methylol -7H- furans [3,2-g] chromene -7- ketone；
The nuclear magnetic data of 5- methylol -7H- furans [3,2-g] chromene -7- ketone (compound 6)：
1H NMR(400MHz,Acetone-d6) δ 7.98 (s, 1H), 7.89 (d, J=2.3Hz, 1H), 7.57 (s, 1H),
6.99 (d, J=2.1,1H), 6.58 (s, 1H), 4.97 (s, 2H)
The preparation of compound 7：
By 0.216g (1mmol) compound 6,1mg 4- dimethylamino pyridines and a drop acetic anhydride are dissolved in drying on a small quantity
It in pyridine, is stirred overnight at room temperature, adds in appropriate ice water, ethyl acetate extraction, organic phase drying, concentration, by residue using column layer
Gradient elution is analysed, eluant, eluent is the petroleum ether of volume ratio 10: 1: ethyl acetate is to get 0.20g compounds 7, (7- oxo -7H- furans
Mutter [3,2-g] chromene -5- bases) methyl acetic acid ester；
The nuclear magnetic data of (7- oxo -7H- furans [3,2-g] chromene -5- bases) methyl acetic acid ester (compound 7)：
1H NMR(400MHz,CDCl3) δ 7.82 (s, 1H), 7.71 (d, J=2.1,1H), 7.47 (s, 1H), 6.86 (d, J
=2.0,1H), 6.49 (s, 1H), 5.37 (s, 2H), 2.23 (s, 3H)
The preparation of compound 8a：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.16g (1.2mmol) 4- methyl benzoic acids are dissolved in suitable dichloromethane
In alkane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 15: 1: ethyl acetate to get 0.30g compound 8a, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(4- methyl) benzoic ether；
The core of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methyl) benzoic ether (compound 8a)
Magnetic data：
1H NMR(600MHz,CDCl3) δ 8.02 (d, J=8.1Hz, 2H), 7.81 (s, 1H), 7.71 (d, J=2.1Hz,
1H), 7.53 (s, 1H), 7.29 (d, J=8.0Hz, 2H), 6.86 (d, J=2.1Hz, 1H), 6.60 (s, 1H), 5.60 (s, 2H),
2.44(s,3H).
13C NMR(101MHz,CDCl3)δ165.77,160.75,156.37,151.71,149.62,147.14,
144.67,129.89,129.40,126.23,124.94,115.46,113.68,111.57,106.57,100.37,61.65,
21.76。
Embodiment 2
The preparation of compound 8b：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.16g (1.2mmol) 2- methyl benzoic acids are dissolved in suitable dichloromethane
In alkane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 15: 1: ethyl acetate to get 0.31g compound 8b, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(2- methyl) benzoic ether；
The core of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methyl) benzoic ether (compound 8b)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.04 (8.04 (dd, J=7.8,0.8Hz, 1H), 7.83 (s, 1H), 7.72 (d, J
=2.1Hz, 1H), 7.54 (s, 1H), 7.50-7.44 (m, 1H), 7.33-7.28 (m, 2H), 6.87 (d, J=2.2Hz, 1H),
6.59(s,1H),5.60(s,2H),2.65(s,3H)；
13C NMR(101MHz,CDCl3)δ166.28,160.68,156.35,151.71,149.55,147.11,
141.04,132.82,132.00,130.76,125.99,124.91,115.45,113.69,111.74,106.53,100.36,
61.61,21.88。
Embodiment 3
The preparation of compound 8c：
The preparation of compound 2- compounds 7 is according to embodiment 1.
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.18g (1.2mmol) 4- methoxy benzoic acids are dissolved in suitable dichloro
In methane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is successively
It is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent
Petroleum ether for volume ratio 15: 1: ethyl acetate is to get 0.32g compound 8c, (7- oxo -7H- furans [3,2-g] benzo pyrrole
Mutter -5-) methyl-(4- methoxyl groups) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methoxyl groups) benzoic ether (compound 8c)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.09 (d, J=8.8Hz, 2H), 7.82 (s, 1H), 7.71 (d, J=2.1Hz,
1H), 7.54 (s, 1H), 6.97 (d, J=8.9Hz, 2H), 6.86 (d, J=2.0Hz, 1H), 6.59 (s, 1H), 5.60 (s, 2H),
3.89(s,3H).
13C NMR(101MHz,CDCl3)δ165.56,160.91,156.52,151.87,149.90,147.28,
132.12,129.20,125.08,121.44,115.62,114.11,113.91,111.67,106.72,100.51,61.68,
55.69。
Embodiment 4
The preparation of compound 8d：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.18g (1.2mmol) O-Anisic Acid are dissolved in suitable dichloro
In methane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is successively
It is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent
Petroleum ether for volume ratio 15: 1: ethyl acetate is to get 0.31g compound 8d, (7- oxo -7H- furans [3,2-g] benzo pyrrole
Mutter -5-) methyl-(2- methoxyl groups) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methoxyl groups) benzoic ether (compound 8d)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.92 (dd, J=7.9,1.8Hz, 1H), 7.82 (s, 1H), 7.71 (d, J=
2.2Hz, 1H), 7.57-7.50 (m, 1H), 7.06-7.00 (m, 2H), 6.86 (d, J=2.2Hz, 1H), 6.73 (s, 1H), 5.60
(s,2H),3.95(s,3H).
13C NMR(101MHz,CDCl3)δ165.56,160.86,159.54,156.33,151.72,149.65,
147.10,134.49,132.20,124.87,120.35,118.61,115.50,113.73,112.11,111.79,106.57,
100.30,61.78,55.94。
Embodiment 5
The preparation of compound 8e：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 4- chlorobenzoic acids are dissolved in suitable dichloromethane
In, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate to get 0.33g compound 8e, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(4- chlorine) benzoic ether；
The nuclear-magnetism of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- chlorine) benzoic ether (compound 8e)
Data：
1H NMR(400MHz,CDCl3) δ 8.07 (d, J=8.6Hz, 2H), 7.80 (s, 1H), 7.72 (d, J=2.3Hz,
1H), 7.55 (s, 1H), 7.48 (d, J=8.6Hz, 2H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.62 (s, 2H)
13C NMR(101MHz,CDCl3)δ164.89,160.63,156.42,151.72,149.20,147.22,
140.40,131.23,129.10,127.41,125.00,115.41,113.58,111.72,106.56,100.46,62.03。
Embodiment 6
The preparation of compound 8f：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 2- chlorobenzoic acids are dissolved in suitable dichloromethane
In, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate to get 0.33g compound 8f, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(2- chlorine) benzoic ether；
The nuclear-magnetism of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- chlorine) benzoic ether (compound 8f)
Data：
1H NMR(400MHz,CDCl3) δ 7.95 (dd, J=7.6,1.3Hz, 1H), 7.82 (s, 1H), 7.72 (d, J=
2.3Hz, 1H), 7.54 (s, 1H), 7.53-7.48 (m, 2H), 7.41-7.35 (m, 1H), 6.87 (d, J=2.2Hz, 1H), 6.64
(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ164.92,160.79,156.55,151.89,149.04,147.33,
134.37,133.55,131.94,131.60,128.88,127.01,125.11,115.68,113.74,112.24,106.71,
100.56,62.57。
Embodiment 7
The preparation of compound 8g：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3,4- dichlorobenzoic acids are dissolved in suitable dichloro
In methane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is successively
It is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent
Petroleum ether for volume ratio 12: 1: ethyl acetate is to get 0.35g compound 8g, (7- oxo -7H- furans [3,2-g] benzo pyrrole
Mutter -5-) methyl-(3,4- dichloros) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,4- dichloros) benzoic ether (compound 8g)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.20 (d, J=2.0Hz, 1H), 7.95 (dd, J=8.4,1.9Hz, 1H), 7.80
(s, 1H), 7.73 (d, J=2.3Hz, 1H), 7.59 (d, J=8.4Hz, 1H), 7.55 (s, 1H), 6.87 (d, J=2.1Hz,
1H),6.55(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ163.97,160.54,158.21,153.31,147.28,143.32,
138.63,136.04,131.73,130.90,128.83,127.59,122.64,120.23,115.41,111.86,106.56,
100.50,62.34。
Embodiment 8
The preparation of compound 8h：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3,5- dichlorobenzoic acids are dissolved in suitable dichloro
In methane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is successively
It is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent
Petroleum ether for volume ratio 12: 1: ethyl acetate is to get 0.35g compound 8h, (7- oxo -7H- furans [3,2-g] benzo pyrrole
Mutter -5-) methyl-(3,5- dichloros) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dichloros) benzoic ether (compound 8h)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=1.9Hz, 2H), 7.79 (s, 1H), 7.73 (d, J=2.2Hz,
1H), 7.62 (t, J=1.9Hz, 1H), 7.55 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.54 (s, 1H), 5.63 (s, 2H)
13C NMR(101MHz,CDCl3)δ163.67,160.63,156.59,151.86,148.84,147.41,
135.83,133.77,131.88,128.96,128.32,125.18,115.52,112.04,106.68,100.63,62.64。
Embodiment 9
The preparation of compound 8i：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.17g (1.2mmol) 4- fluobenzoic acids are dissolved in suitable dichloromethane
In, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate to get 0.30g compound 8i, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(4- fluorine) benzoic ether；
The core of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- fluorine) benzoic ether (compound 8i is)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.19-8.12 (m, 2H), 7.81 (s, 1H), 7.72 (d, J=2.2Hz, 1H),
7.54 (s, 1H), 7.18 (t, J=8.6Hz, 2H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.62 (s, 2H)
13C NMR(101MHz,CDCl3)δ164.87,160.78,156.54,151.85,149.47,147.35,
146.81,132.62,125.13,116.20,115.98,115.56,111.78,106.69,100.56,62.04。
Embodiment 10
The preparation of compound 8j：
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.19g (1.2mmol) 2,4 difluorobenzene formic acid are dissolved in suitable dichloro
In methane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is successively
It is washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent
Petroleum ether for volume ratio 12: 1: ethyl acetate is to get 0.32g compound 8i, (7- oxo -7H- furans [3,2-g] benzo pyrrole
Mutter -5-) methyl-(2,4- difluoros) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2,4- difluoros) benzoic ether (compound 8j)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.08 (td, J=8.5,6.5Hz, 1H), 7.81 (s, 1H), 7.72 (d, J=
2.2Hz, 1H), 7.54 (s, 1H), 7.04-6.90 (m, 2H), 6.87 (d, J=2.0Hz, 1H), 6.63 (s, 1H), 5.63 (s
2H).
13C NMR(101MHz,CDCl3)δ165.18,164.55,162.94,160.79,156.54,151.85,
149.00,147.33,134.41,125.10,115.56,113.67,112.34,112.12,111.97,106.70,105.76,
100.56,62.40。
Embodiment 11
The preparation of compound 8k
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.15g (1.2mmol) benzoic acid are dissolved in suitable dichloromethane, are filled
Point stirring makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor uses 1M hydrochloric acid successively
Solution and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is volume ratio
12: 1 petroleum ether: ethyl acetate is to get 0.29g compound 8i, (7- oxo -7H- furans [3,2-g] chromene -5-) first
Yl benzoic acid ester；
The nuclear magnetic data of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl benzoic acid ester (compound 8k)：
1H NMR(400MHz,CDCl3) δ 8.16-8.11 (m, 2H), 7.82 (s, 1H), 7.72 (d, J=2.2Hz, 1H),
7.64 (t, J=7.4Hz, 1H), 7.56-7.47 (m, 3H), 6.87 (d, J=2.2Hz, 1H), 6.61 (s, 1H), 5.63 (s,
2H).
13C NMR(101MHz,CDCl)δ165.87 160.85,156.54,151.88,149.61,147.32,133.94,
131.04,130.01,128.85,125.11,115.60,113.81,111.79,106.72,100.55,61.96。
Embodiment 12
The preparation of compound 8l
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.20g (1.2mmol) 4- nitrobenzoic acids are dissolved in suitable dichloromethane
In alkane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 12: 1: ethyl acetate to get 0.30g compound 8l, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(4- nitros) benzoic ether；
The core of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- nitros) benzoic ether (compound 8l)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.38-8.26 (m, 5H), 7.81 (s, 1H), 7.73 (d, J=2.3Hz, 1H),
7.56 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.57 (s, 1H), 5.68 (s, 2H)
13C NMR(101MHz,CDCl3)δ165.87,160.85,156.54,151.88,149.61,147.32,
133.94,131.04,130.01,128.85,125.11,115.60,113.81,111.79,106.72,100.55,61.96。
Embodiment 13
The preparation of compound 8m
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 4- trifluoromethylbenzoic acids are dissolved in suitable two
In chloromethanes, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, after raw material all disappears, filtering, mother liquor according to
It is secondary to be washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, elution
Agent is the petroleum ether of volume ratio 12: 1: ethyl acetate is to get 0.34g compound 8m, (7- oxo -7H- furans [3,2-g] benzo
Pyrans -5-) methyl-(4- trifluoromethyls) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- trifluoromethyls) benzoic ether (compound 8m)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 8.25 (d, J=8.0Hz, 2H), 7.81 (s, 1H), 7.77 (d, J=8.3Hz,
2H), 7.73 (d, J=2.3Hz, 1H), 7.56 (s, 1H), 6.87 (d, J=2.2Hz, 1H), 6.58 (s, 1H), 5.66 (s, 2H)
13C NMR(101MHz,CDCl3)δ166.84,160.71,156.60,151.87,149.06,147.42,
137.47,130.44,127.12,125.94,125.18,115.53,112.03,110.18,106.70,100.67,62.48。
Embodiment 14
The preparation of compound 8n
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.23g (1.2mmol) 3- nitrobenzoic acids are dissolved in suitable dichloromethane
In alkane, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor is used successively
1M hydrochloric acid solutions and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is
The petroleum ether of volume ratio 12: 1: ethyl acetate to get 0.31g compound 8n, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(3- nitros) benzoic ether；
The core of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3- nitros) benzoic ether (compound 8n)
Magnetic data：
1H NMR(400MHz,CDCl3) δ 8.52-8.37 (m, 4H), 7.83 (s, 1H), 7.73 (d, J=2.2Hz, 1H),
7.56 (s, 1H), 6.87 (d, J=2.1Hz, 1H), 6.56 (s, 1H), 5.69 (s, 2H)
13C NMR(101MHz,CDCl3)δ164.82,162.22,156.99,156.59,147.46,142.58,
135.51,133.05,130.20,129.53,128.34,125.05,115.55,112.20,109.31,106.70,100.71,
62.77。
Embodiment 15
The preparation of compound 8o
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.25g (1.2mmol) 3,5- dinitrobenzoic acids are dissolved in suitable two
In chloromethanes, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, after raw material all disappears, filtering, mother liquor according to
It is secondary to be washed with 1M hydrochloric acid solutions and saturated sodium bicarbonate solution, dry, concentration, by residue using column chromatography gradient elution, elution
Agent is the petroleum ether of volume ratio 12: 1: ethyl acetate is to get 0.35g compound 8o, (7- oxo -7H- furans [3,2-g] benzo
Pyrans -5-) methyl-(3,5- dinitros) benzoic ether；
(7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dinitros) benzoic ether (compound 8o)
Nuclear magnetic data：
1H NMR(400MHz,CDCl3) δ 9.30 (s, 1H), 9.24-9.21 (m, 2H), 7.83 (s, 1H), 7.74 (d, J=
2.2Hz, 1H), 7.57 (s, 1H), 6.89 (d, J=2.1Hz, 1H), 6.53 (s, 1H), 5.75 (s, 2H)
13C NMR(101MHz,CDCl3)δ165.43,161.05,156.71,152.14,148.89,146.65,
144.81,135.20,132.03,129.76,128.83,124.97,116.08,112.12,107.33,100.36,62.43。
Embodiment 16
The preparation of compound 8p
The preparation of compound 2- compounds 7 is carried out according to embodiment 1：
Under condition of ice bath, by 0.22g (1mmol) compound 6,0.21g (1mmol) dicyclohexylcarbodiimide (DCC),
0.12g (1mmol) 4- dimethylamino pyridines (DMAP) and 0.30g (1.2mmol) 2- iodo-benzoic acids are dissolved in suitable dichloromethane
In, being sufficiently stirred makes it complete molten, moves under room temperature that the reaction was continued, and after raw material all disappears, filtering, mother liquor uses 1M successively
Hydrochloric acid solution and saturated sodium bicarbonate solution washing, dry, concentration, by residue using column chromatography gradient elution, eluant, eluent is body
Petroleum ether of the product than 12: 1: ethyl acetate to get 0.38g compound 8p, (7- oxo -7H- furans [3,2-g] chromene -
5-) methyl-(2- iodine) benzoic ether；
The nuclear-magnetism of (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- iodine) benzoic ether (compound 8p)
Data：
1H NMR(400MHz,CDCl3) δ 8.06 (d, J=8.0Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 7.82 (s,
1H), 7.72 (d, J=1.9Hz, 1H), 7.54 (s, 1H), 7.50-7.42 (m, 2H), 6.87 (d, J=2.0Hz, 1H), 6.62
(s,1H),5.63(s,2H).
13C NMR(101MHz,CDCl3)δ160.79,156.46,149.03,147.35,141.89,133.56,
131.41,128.33,125.13,123.26,116.70,115.69,113.65,112.28,110.17,106.72,100.58,
62.59。
Embodiment 17
Psoralens resistance compound of the present invention is preparing the purposes in treating leucoderma medicament, by embodiment 1-16
The compound 4 of acquisition, 5,6,7,8a-8p measure the melanin content of B16 melanoma cells：
(1) screening model：Murine melanoma cells B16；
(2) cell derived：Chinese Academy of Sciences's cell bank provides；
(3) condition of culture：10% fetal calf serum, 1% dual anti-DMEM in high glucose culture medium add in not afterwards for 24 hours to cultivate cell
With the drug and positive control of concentration, tyrosine activity and melanin content are measured in 48h and 72h respectively；
(4) assay method：
Protein quantification is measured with Bradford methods：
Protein standard substance (5mg/mlBSA) is completely dissolved, 10 μ l is taken to be diluted to 100 μ l, make final concentration of 0.5mg/ml.Egg
For white sample in what solution, standard items also preferably use any solution dilution.But for simplicity 0.9% can also be used
NaCl or PBS dilution standard product；Standard items (0.5mg/mlBSA) are added separately to by 0,1,2,4,8,12,16,20 μ l after diluting
In 96 orifice plates, standard dilutions is added to supply all standard items to 20 μ l；Add proper volume sample to the sample well of 96 orifice plates
In, standard dilutions is added to supply to 20 μ l；Each hole adds in 200 μ l Bradford dyeing liquors, and mixing is gently blown and beaten with sample loading gun
(being careful not to make aeration reading) is placed at room temperature for 3-5 minutes；A595 is measured with microplate reader；It is calculated according to standard curve
Protein concentration in sample；
The content of melanocyte is measured with alkali digestion：
The B16 melanoma cells for being in exponential phase are inoculated in 6cm culture dishes, a concentration of 2 × 105A/ml, respectively
Hole adds 5ml cell suspending liquids；Be inoculated with 12h after, after cell completely it is adherent after medication, Drug level is respectively 5,10,20 and 40 μ g/
ml；Cell is collected after 72h；The 1MNaOH/10%DMSO solution of 200 μ l is added in the case of not smudge cells, puts 80 DEG C
Measure absorption value A in water-bath after 2h at 470nm.Non- medication group (negative control group) is compared as a control group with medication group
It is shown in Table 1；
1 derivative of table is to the antibacterial activity result of melanin genesis in cell and three kinds of bacteriums
As can be seen from the table：Compound 4-7, compound 8a-8d and compound 8k-8o, which are used equally for clinically preparing, to be controlled
Treat the drug of leucoderma.The psoralen ester derivative obtained is used equally for clinically preparing treatment candida albicans infection
Drug, and compound 5 and compound 7 can also be used to clinically preparing the drug for the treatment of infection of staphylococcus aureus.
Claims (3)
1. a kind of psoralen ester derivative, it is characterised in that such derivant structure formula is：
Wherein：
Compound 8a is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methyl) benzoic ether；
Compound 8b is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methyl) benzoic ether；
Compound 8c is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- methoxyl groups) benzoic ether；
Compound 8d is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- methoxyl groups) benzoic ether；
Compound 8e is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- chlorine) benzoic ether；
Compound 8f is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- chlorine) benzoic ether；
Compound 8g is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,4- dichloros) benzoic ether；
Compound 8h is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dichloros) benzoic ether；
Compound 8i is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- fluorine) benzoic ether；
Compound 8j is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2,4- difluoros) benzoic ether；
Compound 8k is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl benzoic acid ester；
Compound 8l is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- nitros) benzoic ether；
Compound 8m is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(4- trifluoromethyls) benzoic ether；
Compound 8n is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3- nitros) benzoic ether；
Compound 8o is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(3,5- dinitros) benzoic ether；
Compound 8p is (7- oxo -7H- furans [3,2-g] chromenes -5-) methyl-(2- iodine) benzoic ether.
2. a kind of psoralen ester derivative as described in claim 1 is in the drug for preparing treatment candida albicans infection
Purposes.
3. a kind of purposes of psoralen ester derivative as described in claim 1 in the drug for preparing treatment leucoderma,
It is characterized in that the psoralen ester derivative is compound 8a-8d and 8k-8o.
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