CN104744510B - Alizarin aminophosphonate ester derivatives and synthetic method thereof and application - Google Patents
Alizarin aminophosphonate ester derivatives and synthetic method thereof and application Download PDFInfo
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- 0 CCOP(C(*C(C(C)Oc(c(O)c1C(c2ccccc22)=O)ccc1C2=O)=O)c(cc1)ccc1F)(OCC)=O Chemical compound CCOP(C(*C(C(C)Oc(c(O)c1C(c2ccccc22)=O)ccc1C2=O)=O)c(cc1)ccc1F)(OCC)=O 0.000 description 2
Abstract
The invention discloses a series of alizarin aminophosphonate ester derivatives and their synthetic method and application.The synthetic method of described alizarin aminophosphonate ester derivatives is: first with alizarin and 2 bromopropionic acid as raw material, it is dissolved in polar solvent, under conditions of acid binding agent potassium hydroxide exists, reaction obtains 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid；Again with 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid and α-aminophosphonicacid ester be raw material, it is dissolved in polar solvent, reacts to completely under conditions of catalyst I-hydroxybenzotriazole and condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride exist；In reactant liquor, add chloroform, washing, collected organic layer, upper silica gel column chromatography purification, to obtain final product.Described alizarin aminophosphonate ester derivatives, shown in its general structure such as following formula (I).
Description
Technical field
The present invention relates to alizarin derivant, be specifically related to alizarin aminophosphonate ester derivatives and synthetic method thereof
And application.
Background technology
Alizarin (Alizarin, chemical name is 1,2-dihydroxy 9,10-anthraquinone), since alizarin is from Radix Rubiae
Root is extracted after purification, and alizarin and derivant thereof have at complete synthesis, structure of modification, biological activity aspect
Research arouse widespread concern.Existing research shows, the concrete blood sugar lowering of alizarin, antiinflammatory,
Antibacterial, the effect of antiviral, also has been reported that alizarin has certain anti-tumor activity.
α-aminophosphonicacid ester is the midbody compound with biological activity and pharmaceutically active, the most by extensively
General for aspects such as antibiotic, antibacterial, enzyme inhibitor and herbicides.But have not yet to see madder
Element introduces the derivant of this functional group of α-aminophosphonicacid ester and this analog derivative at anti-tumor aspect
Open report.
Summary of the invention
The technical problem to be solved in the present invention is to provide the novel alizarin amido phosphonate of a class formation and derives
Thing, and their synthetic method and application.
Alizarin aminophosphonate ester derivatives of the present invention, shown in its general structure such as following formula (I):
Wherein, R be to bromobenzene, bromophenyl, a bromobenzene, to fluorobenzene, adjacent fluorobenzene, to chlorobenzene, m-chloro
Benzene, adjacent chlorobenzene, meta-methoxy benzene, O-methoxy benzene, benzene, 1-naphthalene, to methoxybenzene, a methylbenzene,
To methylbenzene, a fluorobenzene or 2-naphthalene.
Corresponding to the selection of above-mentioned R, logical formula (I) compound may is that
(a) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl ammonia
Base] (4-bromophenyl) methyl } diethyl phosphonate；
(b) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl ammonia
Base] (2-bromophenyl) methyl } diethyl phosphonate；
(c) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (3-bromophenyl) methyl } diethyl phosphonate；
(d) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (4-fluorophenyl) methyl } diethyl phosphonate；
(e) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (2-fluorophenyl) methyl } diethyl phosphonate；
(f) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (4-chlorphenyl) methyl } diethyl phosphonate；
(g) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (3-chlorphenyl) methyl } diethyl phosphonate；
(h) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (2-chlorphenyl) methyl } diethyl phosphonate；
(i) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (3-methoxyphenyl) methyl } diethyl phosphonate；
(j) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (2-methoxyphenyl) methyl } diethyl phosphonate；
(k) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (phenyl) methyl } diethyl phosphonate；
(l) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (1-naphthyl) methyl } diethyl phosphonate；
(m) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (4-methoxyphenyl) methyl } diethyl phosphonate；
(n) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (3-aminomethyl phenyl) methyl } diethyl phosphonate；
(o) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (4-tolyl) methyl } diethyl phosphonate；
(p) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (3-fluorophenyl) methyl } diethyl phosphonate；
(q) O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl) propionyl
Amino] (2-naphthyl) methyl } diethyl phosphonate.
The synthetic method of above-mentioned alizarin aminophosphonate ester derivatives comprises the following steps:
1) with alizarin and 2 bromopropionic acid as raw material, it is dissolved in polar solvent, exists at acid binding agent potassium hydroxide
Under conditions of react to completely, in reactant liquor, add ethyl acetate, washing, collect water layer, by water layer
It is adjusted to acidity, has Precipitation, filter, collect precipitation, washing, be dried, obtain 2-(1-hydroxyl-9,10-
Dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid；
2) with 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid and alpha-amido
Phosphonate ester is raw material, is dissolved in polar solvent, at catalyst I-hydroxybenzotriazole and condensing agent 1-(3-
Dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride exist under conditions of react to completely；To reactant liquor
Middle addition chloroform, washing, collected organic layer, upper silica gel column chromatography, with by volume ratio be 1:4～
The ethyl acetate of 100 and the mixed solvent eluting of petroleum ether composition, eluent solvent evaporated, i.e. obtain phase
The alizarin aminophosphonate ester derivatives answered.
In above-mentioned synthetic method, corresponding to alizarin aminophosphonate ester derivatives, described α-aminophosphonicacid ester
It is chosen as:
α-O, O' diethylamino (4-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-fluorophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-fluorophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (phenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (1-naphthyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-aminomethyl phenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-tolyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-fluorophenyl) methylphosphonic acid diethylester；Or
α-O, O' diethylamino (2-naphthyl) methylphosphonic acid diethylester.
The synthesis of above-mentioned α-aminophosphonicacid ester refer to existing document (B.Kaboudin, K.Moradi,
Tetrahydron Lett.46 (2005) 2989-2991) carry out.Concrete synthetic method may is that
Aldehyde (selecting different aldehyde according to different α-aminophosphonicacid esters), ammonium acetate and phosphorous acid two is added in flask
Ethyl ester (wherein the mol ratio of aldehyde, ammonium acetate and diethyl phosphite is 2～3:1～1.5:1～1.5,
Under the conditions of 80～90 DEG C, stir 10～12h, then (addition of ether is toward addition ether in this flask
1～1.5 times of the amount of the material of aldehyde), add concentrated hydrochloric acid under ice bath and make reaction system in acid (pH=5～6)
And stirring 2～3h, system use water extracts, and collects water layer and removes organic impurities with ether extraction again, then receives
Collection water layer, and adding sodium hydroxide solution in the water layer collected, to regulate its pH be 8～10, uses acetic acid second
Ester (or ether) extract, collected organic layer, organic layer is dried through anhydrous sodium sulfate, obtain corresponding α-
Amido phosphonate, all of α-aminophosphonicacid ester is pale yellow oily liquid body.In this synthetic method, aldehyde
Be chosen as: p-bromobenzaldehyde, o-bromobenzaldehye, 3-bromobenzaldehyde, 4-Fluorobenzaldehyde, adjacent fluorobenzene first
Aldehyde, 4-chloro-benzaldehyde, m chlorobenzaldehyde, o-chlorobenzaldehyde, m-methoxybenzaldehyde, O-methoxy benzene
Formaldehyde, benzaldehyde, 1-naphthaldehyde, P-methoxybenzal-dehyde, a tolyl aldehyde, p-tolyl aldehyde,
Between fluorobenzaldehyde or 2-naphthaldehyde.
In above-mentioned synthetic method, described polar solvent is selected from dimethyl sulfoxide, N, N-dimethyl formyl
One in amine, ethyl acetate, methanol, ethanol, propanol, butanol, dichloromethane and chloroform or
The most two or more combinations.When the combination being chosen as more than above two of polar solvent, they it
Between proportioning can be any proportioning.Step 1) in, specifically when dissolving, can be first by molten for alizarin polarity
After agent is dissolved, add 2 bromopropionic acid and remix together；Also alizarin and 2 bromopropionic acid can be blended in one
Add polar solvent after Qiing to dissolve；Potassium hydroxide is typically to be directly added in solid form.Polar solvent
Consumption can determine as required, typically so that the amount of reaction raw materials can be dissolved, it is generally the case that 1
The alizarin of the mmol polar solvent of 5～20mL dissolves.Step 2) in, specifically when dissolving, can
By 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid and α-aminophosphonicacid ester
Dissolve with polar solvent respectively, remix together；Also can be by 2-(1-hydroxyl-9,10-dioxo-9,10-
Dihydroanthracene-2-base epoxide) propanoic acid and α-aminophosphonicacid ester add polar solvent and dissolve after mixing；
Can also be by 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid polarity is molten
After agent is dissolved, it is directly added into α-aminophosphonicacid ester solid.The consumption of polar solvent can determine as required,
General so that the amount of reaction raw materials can be dissolved, it is generally the case that 2-(1-hydroxyl-9 of 1mmol, 10-
Dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid or 1mmol α-aminophosphonicacid ester be with 5～20mL
Polar solvent dissolve.
The step 1 of above-mentioned synthetic method) in, alizarin, 2 bromopropionic acid are the material of raw material and potassium hydroxide
The ratio of amount is preferably 1:1:3～5.Reaction is preferably carried out under conditions of less than 50 DEG C, preferably exists
Carry out under conditions of 10～40 DEG C, more preferably carry out under conditions of 20～40 DEG C.React the most complete
Can use thin layer chromatography tracing detection, under the conditions of above-mentioned preferred reaction temperature, stirring reaction is to completely
Take around the time of 0.5～5 day.In order to improve the productivity of reaction, preferably potassium hydroxide is divided 2～
3 batches (every minor tick 10～48h) adds.In this step, it is common that with hydrochloric acid, sulphuric acid, phosphoric acid or nitric acid
Deng other mineral acid, water layer being adjusted to acidity, preferably water layer being transferred to pH is 2～6.
The step 2 of above-mentioned synthetic method) in, 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) metering that ratio the is chemical equation ratio of amount of material of propanoic acid and α-aminophosphonicacid ester is 1:
1。
The step 2 of above-mentioned synthetic method) in, the addition of described catalyst I-hydroxybenzotriazole (HOBT)
For 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) amount of propanoic acid material 0.05～
0.5 times, preferably 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid material
0.05～0.2 times of amount, more preferably 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) 0.1～0.2 times of amount of propanoic acid material.Owing to the membership that adds of catalyst produces exothermic reaction,
The most described catalyst is preferably and adds under condition of ice bath.Described condensing agent 1-(3-dimethylamino third
Base) addition of-3-ethyl-carbodiimide hydrochloride (EDAC) is 2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-base epoxide) 1～2 times of amount of propanoic acid material, preferably 2-(1-hydroxyl-9,10-
Dioxo-9,10-dihydroanthracene-2-base epoxide) 1～1.5 times of amount of propanoic acid material.
Step 2 in synthetic method described herein) in, 2-(1-hydroxyl-9,10-dioxo-9,10-
Dihydroanthracene-2-base epoxide) propanoic acid, α-aminophosphonicacid ester, the charging sequence of catalyst and condensing agent do not has
Particularly be particular about, but higher yield can be obtained with following charging sequence: first by 2-(1-hydroxyl
-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) after propanoic acid dissolves, add catalyst, stir,
Then adding condensing agent, (now α-aminophosphonicacid ester can to add α-aminophosphonicacid ester after stirring
To add in solid form, it is also possible to add in fluid form after it is dissolved with polar solvent) carry out
Reaction.
The step 2 of above-mentioned synthetic method) in, reaction is preferably carried out, more preferably under conditions of less than 80 DEG C
It is to carry out under conditions of 20～40 DEG C.Reaction can use thin layer chromatography tracing detection, the most completely upper
Under the conditions of stating preferred reaction temperature, stirring reaction is to the time taking around 3～5h completely.
The step 2 of above-mentioned synthetic method) in, described in the mixed solvent of eluting, ethyl acetate and stone
The volume ratio of oil ether is preferably 1:4～50, more preferably 1:4～20, more preferably 1:4～
10, most preferably 1:4～6.
Present invention additionally comprises the application in preparing antitumor drug of the above-mentioned alizarin aminophosphonate ester derivatives.
Present invention additionally comprises the antineoplastic agent prepared with above-mentioned alizarin aminophosphonate ester derivatives for effective ingredient
Thing.
Compared with prior art, the alizarin amido phosphonate that the invention provides a series of novel structure derives
Thing, and their its synthetic method and application.It is found by the applicant that most alizarin amido phosphonate spreads out
The anti-tumor activity that biology has is all higher than its parent alizarin, has preferable potential medical value, is expected to
Preparation for various antitumor drug.
Detailed description of the invention
With specific embodiment, the invention will be further described below, but the invention is not limited in that these are real
Execute example.
Embodiment 1:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (4-bromophenyl) methyl } synthesis of diethyl phosphonate (a)
1) synthesis of α-O, O' diethylamino (4-bromophenyl) methylphosphonic acid diethylester
Round-bottomed flask adds p-bromobenzaldehyde, ammonium acetate and diethyl phosphite (mol ratio is 2:1:
1), stirring reaction 10h under the conditions of 80 DEG C, then be to bromine toward addition ether addition in this round-bottomed flask
1.2 times of the amount of the material of benzaldehyde), add concentrated hydrochloric acid under ice bath and make reaction system in acid (pH=6) and stir
Mixing 3h, reaction system use water extracts, and collects water layer and removes organic impurities with ether extraction again, regathers
Water layer, and adding the sodium hydroxide solution that mass concentration is 10% in the water layer collected, to regulate its pH be 9,
Being extracted with ethyl acetate, collected organic layer, organic layer is dried through anhydrous sodium sulfate, obtains α-O, O' bis-
Ethylamino (4-bromophenyl) methylphosphonic acid diethylester.
2) synthesis of target product:
2.1) in round-bottomed flask, 2.2mmol alizarin is dissolved in 15mL dimethyl sulfoxide, is subsequently adding
6.6mmol acid binding agent potassium hydroxide (adds) in solid form, adds 2.2mmol2-bromo-propionic acid, room
Under the conditions of temperature, stirring reaction is to completely (about 4 days), then adds ethyl acetate in reactant liquor, washes,
Collecting water layer, water layer hydrochloric acid is adjusted to acidity (pH=5), has orange Precipitation, filter, it is heavy to collect
Form sediment, be washed to neutrality, be dried, obtain 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base
Epoxide) propanoic acid；1H NMR(DMSO,500MHz):13.10(s,1H),8.29-8.16(m,2H),
7.99-7.89(m,2H),7.72(d,J=8.4Hz,1H),7.31(d,J=8.5Hz,1H),
5.09(q,J=6.8Hz,1H),1.60(d,J=6.8Hz,3H);FAB-MS m/z:313
[M+H]+;Anal.Calcd.C17H12O6:C,65.39;H,3.87.Found:C,65.43;H,
3.82.
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 5mL dimethyl sulfoxide, drips 0.5mmol catalyst 1-hydroxyl under ice bath
Benzotriazole, is stirred at room temperature 10min, is subsequently adding 1.1mmol condensing agent 1-(3-dimethylamino-propyl)-3-
Ethyl-carbodiimide hydrochloride, continues stirring 10min；1mmol α-O is dripped again in this round-bottomed flask,
O' diethylamino (4-bromophenyl) methylphosphonic acid diethylester (is made into molten with 5mL dmso solution
Liquid, adds in the way of solution), under room temperature condition, stirring reaction is to completely (about 4h), then to reaction
Adding chloroform in liquid, washing, collected organic layer, organic layer goes up silica gel after drying with anhydrous sodium sulfate
Column chromatography, with ethyl acetate: the mixed solvent eluting that petroleum ether=1:5 (volume ratio) forms, thin layer chromatography
Tracing detection, collects eluent, eluent solvent evaporated, obtains orange solids a.
Being analyzed gained orange solids a, its physics and chemistry and spectral characteristic are as follows:
Yields79.12%;1H NMR(500MHz,CDCl3)δ13.05(s,-OH,1H),
8.33–8.28(m,Ar-H,2H),8.03–7.90(m,Ar-H,1H),7.86–7.76(m,Ar-H,
3H),7.51(d,Ar-H,J=8.3Hz,1H),7.35(dd,Ar-H,J=8.5,2.1Hz,
2H),7.23(m,Ar-H,1H,NH,1H),5.40(dd,PCH,J=20.8,9.1Hz,1H),
4.85(dd,OCHCO,J=27.8,6.9Hz,1H),4.20–3.77(m,OCH2,4H),1.65
(d,CH3,J=6.8Hz,3H),1.15(t,OCH3,J=7.1Hz,3H),1.09(t,OCH3,
J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ189.03,181.30,170.61,
168.40,153.32,151.20,135.03,134.04,133.76,133.33,131.87,131.68,
129.50,129.45,127.50,127.21,127.00,121.10,121.02,120.53,116.93,
77.32,63.50,63.08,50.06,18.65,16.25,16.20;31P NMR(202MHz,CDCl3)
δ20.29;ESI–MS m/z:616.1(M+H)+;Anal.Calc.(for C28H27BrNO8P):
C,54.56;H,4.42;N,2.27;Found:C,54.60;H,4.52;N,2.29.
Accordingly, it can be determined that gained orange solids a is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (4-bromophenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 2:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen methyl)
Propionamido] (2-bromophenyl) methyl } synthesis of diethyl phosphonate (b)
1) synthesis of α-O, O' diethylamino (2-bromophenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, use bromophenyl
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL DMF, drips 0.1mmol catalyst under ice bath
I-hydroxybenzotriazole, is stirred at room temperature 3min, is subsequently adding 1.5mmol condensing agent 1-(3-dimethylamino
Propyl group)-3-ethyl-carbodiimide hydrochloride, continues stirring 13min；1 is dripped again in this round-bottomed flask
Mmol α-O, O' diethylamino (2-bromophenyl) methylphosphonic acid diethylester is (sub-with 5mL dimethyl
Sulfone dissolves wiring solution-forming, adds in the way of solution), under room temperature condition, stirring reaction is to complete (about 4h),
Then adding chloroform, washing, collected organic layer in reactant liquor, organic layer anhydrous sodium sulfate is done
Upper silica gel column chromatography after dry, with ethyl acetate: the mixed solvent eluting that petroleum ether=1:4 (volume ratio) forms,
Thin layer chromatography tracing detection, collects eluent, eluent solvent evaporated, obtains orange solids b.
Being analyzed gained orange solids b, its physics and chemistry and spectral characteristic are as follows:
Yields88.44%;1H NMR(500MHz,CDCl3)δ12.98(s,-OH,1H),
8.34–8.27(m,Ar-H,2H),8.01(dd,Ar-H,J=9.1,4.7Hz,1H),
7.85–7.76(m,Ar-H,3H),7.74(s,Ar-H,1H),7.42–7.33(m,Ar-H,2H),
7.16–7.02(m,Ar-H,1H,NH,1H),6.06(dd,PCH,J=20.9,9.2Hz,1H),
4.83(dd,OCHCO,J=28.0,6.8Hz,1H),4.23–3.67(m,OCH2,4H),1.73
(d,CH3,J=6.7Hz,3H),1.36(t,OCH3,J=7.1Hz,3H),1.11(t,OCH3,
J=7.0Hz,3H);13C NMR(125MHz,CDCl3)δ188.99,181.27,170.60,
167.36,153.15,151.15,134.97,134.44,134.00,133.76,133.01,129.63,
129.09,127.66,127.46,126.94,126.57,124.46,120.86,120.57,116.76,
77.25,63.81,63.55,49.75,18.64,16.34,16.04;31P NMR(202MHz,CDCl3)
δ20.32;ESI–MS m/z:616.1(M+H)+;Anal.Calc.(for C28H27BrNO8P):
C,54.56;H,4.42;N,2.27;Found:C,54.51;H,4.50;N,2.31.
Accordingly, it can be determined that gained orange solids b is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (2-bromophenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 3:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (3-bromophenyl) methyl } synthesis of diethyl phosphonate (c)
1) synthesis of α-O, O' diethylamino (3-bromophenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with between bromobenzene
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL methanol, drips 0.05mmol catalyst 1-hydroxy benzo under ice bath
Triazole, is stirred at room temperature 5min, is subsequently adding 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide hydrochloride, continues stirring 3min；1mmol α-O, O' bis-is dripped again in this round-bottomed flask
Ethylamino (3-bromophenyl) methylphosphonic acid diethylester (dissolves wiring solution-forming with 20mL ethanol, with molten
The mode of liquid adds), under room temperature condition, stirring reaction is to completely (about 4h), then adds in reactant liquor
Chloroform, washes, collected organic layer, and organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate,
With ethyl acetate: the mixed solvent eluting that petroleum ether=1:6 (volume ratio) forms, thin layer chromatography tracing detection,
Collect eluent, eluent solvent evaporated, obtain orange solids c.
Being analyzed gained orange solids c, its physics and chemistry and spectral characteristic are as follows:
Yields86.12%;1H NMR(500MHz,CDCl3)δ13.02(s,-OH,1H),
8.34–8.25(m,Ar-H,2H),8.00–7.92(m,Ar-H,1H),7.84–7.73(m,Ar-H,
3H),7.47–7.26(m,Ar-H,4H),7.22–7.10(m,NH,1H),5.45(dd,PCH,
J=20.13,8.3Hz,1H),4.89(q,OCHCO,J=30.6,13.6Hz,1H),
4.19–3.93(m,OCH2,4H),1.66(d,CH3,J=6.7Hz,3H),1.17(t,OCH3,
J=7.2Hz,3H),1.09(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)
δ188.99,181.29,170.66,153.40,151.22,134.97,134.01,133.78,
133.11,131.29,131.18,130.97,130.86,130.23,129.99,127.46,126.98,
126.63,122.68,121.31,116.92,77.41,68.27,63.15,48.89,18.56,
16.18,16.07;ESI–MS m/z:616.1(M+H)+;Anal.Calc.(for C28H27BrNO8P):
C,54.56;H,4.42;N,2.27;Found:C,54.59;H,4.40;N,2.31.
Accordingly, it can be determined that gained orange solids c is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (3-bromophenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 4:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (4-fluorophenyl) methyl } synthesis of diethyl phosphonate (d)
1) synthesis of α-O, O' diethylamino (4-fluorophenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with to fluorobenzene
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in mixed solution (dichloromethane and three chloromethanes of 10mL dichloromethane and chloroform
The volume ratio of alkane is 1:1) in, under ice bath, drip 0.2mmol catalyst I-hydroxybenzotriazole, room
Temperature stirring 8min, is subsequently adding 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide
Hydrochlorate, continues stirring 3min；1mmol α-O, O' diethyl amino is dripped again in this round-bottomed flask
Base (4-fluorophenyl) methylphosphonic acid diethylester (dissolves wiring solution-forming with 10mL chloroform, with solution
Mode adds), under room temperature condition, stirring reaction is to completely (about 4.5h), then adds three in reactant liquor
Chloromethanes, washes, collected organic layer, and organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with
Ethyl acetate: the mixed solvent eluting that petroleum ether=1:20 (volume ratio) forms, thin layer chromatography tracing detection,
Collect eluent, eluent solvent evaporated, obtain orange solids d.
Being analyzed gained orange solids d, its physics and chemistry and spectral characteristic are as follows:
Yields84.44%;1H NMR(500MHz,CDCl3)δ13.01(s,-OH,1H),
8.31–8.26(m,Ar-H,2H),7.90(dd,Ar-H,J=9.3,4.5Hz,1H),
7.83–7.72(m,Ar-H,3H),7.48–7.39(m,Ar-H,2H),7.24(d,NH,J=
5.5Hz,1H),7.05(t,Ar-H,J=8.6Hz,2H),5.43(dd,PCH,J=20.7,
9.5Hz,1H),4.89–4.84(dd,OCHCO,J=31.4,6.5Hz,1H),4.16–3.72
(m,OCH2,4H),1.63(d,CH3,J=6.8Hz,3H),1.13(t,OCH3,J=7.1
Hz,3H),1.05(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ189.07,
181.35,170.58,153.46,151.29,135.04,134.07,133.85,133.17,130.49,
129.69,129.58,127.54,127.34,127.04,121.31,120.54,116.99,115.85,
115.68,115.50,77.40,63.41,63.04,49.92,18.60,16.24,16.14;31P
NMR(202MHz,Acetone)δ20.70;ESI–MS m/z:554.1(M–H)—;Anal.
Calc.(for C28H27FNO8P):C,60.54;H,4.90;N,2.52;Found:C,60.63;
H,4.89;N,2.50.
Accordingly, it can be determined that gained orange solids d is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (4-fluorophenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 5:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (2-fluorophenyl) methyl } synthesis of diethyl phosphonate (e)
1) synthesis of α-O, O' diethylamino (2-fluorophenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with adjacent fluorobenzene
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in the mixed solution of 5mL ethyl acetate, drips 0.08mmol catalysis under ice bath
Agent I-hydroxybenzotriazole, is stirred at room temperature 5min, is subsequently adding 1.8mmol condensing agent 1-(3-diformazan ammonia
Base propyl group)-3-ethyl-carbodiimide hydrochloride, continues stirring 13min；1 is dripped again in this round-bottomed flask
Mmol α-O, O' diethylamino (2-fluorophenyl) methylphosphonic acid diethylester is (molten by 10mL ethyl acetate
Solve wiring solution-forming, add in the way of solution), under room temperature condition, stirring reaction is to complete (about 4h), so
Adding chloroform in backward reactant liquor, washing, collected organic layer, organic layer anhydrous sodium sulfate is dried
Rear upper silica gel column chromatography, with ethyl acetate: the mixed solvent eluting that petroleum ether=1:10 (volume ratio) forms,
Thin layer chromatography tracing detection, collects eluent, eluent solvent evaporated, obtains orange solids e.
Being analyzed gained orange solids e, its physics and chemistry and spectral characteristic are as follows:
Yields76.90%;1H NMR(500MHz,CDCl3)δ13.05(s,-OH,1H),
8.35–8.28(m,Ar-H,2H),8.06–7.90(m,Ar-H,1H),7.87–7.73(m,Ar-H,
3H),7.52–7.29(m,Ar-H,2H),7.21–6.94(m,Ar-H,2H,NH,1H),5.82
(dd,PCH,J=21.0,9.5Hz,1H),4.88(dd,OCHCO,J=32.4,6.5Hz,
1H),4.21–3.81(m,OCH2,4H),1.65(d,CH3,J=6.4Hz,3H),1.16(m,
OCH3,J=6.9Hz,3H),1.09(t,OCH3,J=6.8Hz,3H);13C NMR(125MHz,
CDCl3)δ189.00,181.32,170.57,163.18,153.31,151.28,135.01,
134.05,133.79,133.13,132.80,129.89,129.75,129.58,129.48,129.07,
127.48,127.37,127.01,120.78,120.58,77.13,63.85,63.41,47.19,
18.55,16.29,16.10;31P NMR(202MHz,CDCl3)δ20.25;ESI–MS m/z:
554.1(M–H)—;Anal.Calc.(for C28H27FNO8P):C,60.54;H,4.90;N,
2.52;Found:C,60.61;H,4.93;N,2.53.
Accordingly, it can be determined that gained orange solids e is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-
Dihydroanthracene-2-oxygen methyl) propionamido] (2-fluorophenyl) methyl } diethyl phosphonate, its structural formula such as following formula
Shown in:
Embodiment 6:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (4-chlorphenyl) methyl } synthesis of diethyl phosphonate (f)
1) synthesis of α-O, O' diethylamino (4-chlorphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with to chlorobenzene
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in mixed solution (ethyl acetate and the volume ratio of methanol of 8mL ethyl acetate and methanol
For 2:1) in, under ice bath, drip 0.08mmol catalyst I-hydroxybenzotriazole, 5min be stirred at room temperature,
It is subsequently adding 1.8mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continues
Stirring 13min；1mmol α-O, O' diethylamino (4-chlorphenyl) is dripped again in this round-bottomed flask
Methylphosphonic acid diethylester (dissolves wiring solution-forming with 4mL methanol and 1mL ethanol, add in the way of solution),
Under room temperature condition, stirring reaction is to completely (about 3.5h), then adds chloroform in reactant liquor, washes,
Collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with ethyl acetate: oil
The mixed solvent eluting that ether=1:8 (volume ratio) forms, thin layer chromatography tracing detection, collect eluent, wash
De-liquid solvent evaporated, obtains orange solids f.
Being analyzed gained orange solids f, its physics and chemistry and spectral characteristic are as follows:
Yields83.72%;1H NMR(500MHz,CDCl3)δ12.99(s,-OH,1H),
8.30–8.22(m,Ar-H,2H),8.11(dd,Ar-H,J=9.3,3.9Hz,1H),
7.99-7.75(m,Ar-H,4H),7.41–7.32(m,Ar-H,3H),7.26–7.20(m,NH,
1H),5.46(dd,PCH,J=21.1,9.5Hz,1H),4.88(dd,OCHCO,J=31.6,
6.4Hz,1H),4.08–3.71(m,OCH2,4H),1.63(d,CH3,J=6.8Hz,3H),
1.14(t,OCH3,J=7.1Hz,3H),1.06(t,OCH3,J=7.1Hz,3H);13C NMR
(125MHz,CDCl3)δ188.96,181.25,170.89,170.83,163.11,153.28,
151.21,134.95,133.98,133.72,133.05,132.81,129.24,129.19,128.92,
128.75,127.43,126.93,121.06,120.48,116.82,77.11,63.80,63.43,
49.92,18.54,16.13,16.02;31P NMR(202MHz,CDCl3)δ20.45;ESI–MS
m/z:570.1(M–H)—;Anal.Calc.(for C28H27ClNO8P):C,58.80;H,4.76;
N,2.45;Found:C,58.70;H,4.72;N,2.49.
Accordingly, it can be determined that gained orange solids f is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (4-chlorphenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 7:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (3-chlorphenyl) methyl } synthesis of diethyl phosphonate (g)
1) synthesis of α-O, O' diethylamino (3-chlorphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with between chlorobenzene
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 1；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in mixed solution (N, the N-dimethyl methyl of 10mL N,N-dimethylformamide and ethanol
The volume ratio of amide and ethanol is 1:5) in, under ice bath, drip 0.4mmol catalyst 1-hydroxy benzo
Triazole, is stirred at room temperature 10min, is subsequently adding 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide hydrochloride, continues stirring 13min；1mmol α-O, O' is dripped again in this round-bottomed flask
(with 5mLN, dinethylformamide dissolves and is made into diethylamino (3-chlorphenyl) methylphosphonic acid diethylester
Solution, adds in the way of solution), under room temperature condition, stirring reaction is to completely (about 4h), then to instead
Answering addition chloroform in liquid, washing, collected organic layer, organic layer goes up silicon after drying with anhydrous sodium sulfate
Plastic column chromatography, with ethyl acetate: the mixed solvent eluting that petroleum ether=1:50 (volume ratio) forms, thin layer
Chromatography tracing detection, collects eluent, eluent solvent evaporated, obtains orange solids g.
Being analyzed gained orange solids g, its physics and chemistry and spectral characteristic are as follows:
Yields89.42%;1H NMR(500MHz,CDCl3)δ13.06(s,-OH,1H),
8.36–8.26(m,Ar-H,2H),7.97(dd,Ar-H,J=9.3,4.8Hz,1H),
7.85–7.74(m,Ar-H,3H),7.46–7.27(m,Ar-H,4H),7.17(d,NH,J=
8.0Hz,1H),5.43(dd,PCH,J=21.1,9.4Hz,1H),4.90(dd,OCHCO,
J=6.8,1.2Hz,1H),4.09–3.77(m,OCH2,4H),1.67(d,CH3,J=6.8
Hz,3H),1.16(t,OCH3,J=7.1Hz,3H),1.09(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ189.03,181.34,170.63,153.38,151.22,
136.61,135.03,134.58,134.06,133.77,133.10,129.98,128.45,127.96,
127.51,127.26,127.01,126.01,121.21,120.52,116.92,77.32,63.46,
63.10,48.93,18.60,16.20,16.10;ESI–MS m/z:570.1(M–H)—;Anal.
Calc.(for C28H27ClNO8P):C,58.80;H,4.76;N,2.45;Found:C,58.82;
H,4.78;N,2.51.
Accordingly, it can be determined that gained orange solids g is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (3-chlorphenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 8:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (2-chlorphenyl) methyl } synthesis of diethyl phosphonate (h)
1) synthesis of α-O, O' diethylamino (2-chlorphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with adjacent chlorobenzene
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) in round-bottomed flask, 3.3mmol alizarin is dissolved in 20mL dimethyl sulfoxide, adds
3.3mmol2-bromo-propionic acid, adds 13.2mmol acid binding agent potassium hydroxide and (adds in solid form, divide 2
Criticize and add, every crowd of interval 24h), under the conditions of 40 DEG C, under room temperature condition, stirring is reacted to complete (about 3 days),
Then in reactant liquor, add ethyl acetate, washing, collect water layer, water layer sulphuric acid is adjusted to acidity
(pH=2), there is orange Precipitation, filter, collect precipitation, be washed to neutrality, be dried, obtain 2-(1-
Hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid；1H NMR(DMSO,500MHz):
13.10(s,1H),8.29-8.16(m,2H),7.99-7.89(m,2H),7.72(d,J=8.4
Hz,1H),7.31(d,J=8.5Hz,1H),5.09(q,J=6.8Hz,1H),1.60(d,
J=6.8Hz,3H);FAB-MS m/z:313[M+H]+;Anal.Calcd.C17H12O6:C,65.39;
H,3.87.Found:C,65.43;H,3.82.
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL DMF, drips 0.5mmol catalyst under ice bath
I-hydroxybenzotriazole, is stirred at room temperature 6min, is subsequently adding 1mmol condensing agent 1-(3-dimethylamino third
Base)-3-ethyl-carbodiimide hydrochloride, continues stirring 5min；1mmol is dripped again in this round-bottomed flask
α-O, O' diethylamino (2-chlorphenyl) methylphosphonic acid diethylester (is joined with 5mL acetic acid ethyl dissolution
Become solution, add in the way of solution), under room temperature condition, stirring reaction is to completely (about 4h), then to
Reactant liquor adds chloroform, washing, collected organic layer, organic layer with anhydrous sodium sulfate dried on
Silica gel column chromatography is with ethyl acetate: the mixed solvent eluting that petroleum ether=1:100 (volume ratio) forms, thin
Analyse tracing detection layer by layer, collect eluent, eluent solvent evaporated, obtain orange solids h.
Being analyzed gained orange solids h, its physics and chemistry and spectral characteristic are as follows:
Yields83.18%;1H NMR(500MHz,CDCl3)δ13.00(s,-OH,1H),
8.30–8.21(m,Ar-H,2H),8.13(dd,Ar-H,J=9.3,4.6Hz,1H),
7.83–7.70(m,Ar-H,3H),7.57(dd,Ar-H,J=7.7,1.9Hz,1H),
7.39–7.24(m,Ar-H,3H),7.16–7.08(m,NH,1H),6.06(dd,PCH,J=
21.0,9.3Hz,1H),4.96–4.87(dd,OCHCO,J=20.8,6.6Hz,1H),
4.23–3.69(m,OCH2,4H),1.62(d,CH3,J=6.8Hz,3H),1.17(t,OCH3,
J=7.1Hz,3H),1.04(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)
δ188.99,181.31,170.62,163.17,153.29,151.27,135.00,134.04,
133.77,133.11,132.78,129.88,129.73,129.57,129.47,129.05,127.46,
127.37,126.99,120.76,120.57,77.12,63.83,63.40,47.18,18.70,
16.23,16.04;31P NMR(202MHz,CDCl3)δ20.31;ESI–MS m/z:570.1(M
–H)—;Anal.Calc.(for C28H27ClNO8P):C,58.80;H,4.76;N,2.45;Found:
C,58.84;H,4.79;N,2.50.
Accordingly, it can be determined that gained orange solids h is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (2-chlorphenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 9:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen first
Base) propionamido] (3-methoxyphenyl) methyl } synthesis of diethyl phosphonate (i)
1) synthesis of α-O, O' diethylamino (3-methoxyphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with between methoxy
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 8；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 20mL dimethyl sulfoxide, drips 0.3mmol catalyst 1-hydroxyl under ice bath
Benzotriazole, is stirred at room temperature 6min, is subsequently adding 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-
Ethyl-carbodiimide hydrochloride, continues stirring 10min；1mmol α-O is dripped again in this round-bottomed flask,
O' diethylamino (3-methoxyphenyl) methylphosphonic acid diethylester (uses 5mL N,N-dimethylformamide
Dissolve wiring solution-forming, add in the way of solution), under the conditions of 40 DEG C, stirring reaction is to complete (about 3h),
Then adding chloroform, washing, collected organic layer in reactant liquor, organic layer anhydrous sodium sulfate is done
Upper silica gel column chromatography after dry, with ethyl acetate: the mixed solvent that petroleum ether=1:30 (volume ratio) forms is washed
De-, thin layer chromatography tracing detection, collect eluent, eluent solvent evaporated, obtain orange solids i.
Being analyzed gained orange solids i, its physics and chemistry and spectral characteristic are as follows:
Yields83.16%;1H NMR(500MHz,CDCl3)δ13.03(s,-OH,1H),
8.33–8.23(m,Ar-H,2H),8.05–7.99(m,Ar-H,1H),7.83–7.71(m,Ar-H,
3H),7.29–7.22(m,Ar-H,2H),7.04(d,NH,J=7.6Hz,1H),6.84(dd,
Ar-H,J=16.7,8.0Hz,2H),5.46(dd,PCH,J=20.7,9.6Hz,1H),4.89
(dd,OCHCO,J=6.7,0.9Hz,1H),3.96–3.83(m,OCH2,4H),3.81(s,
OCH3,3H),1.66(d,CH3,J=6.8Hz,3H),1.15(t,OCH3,J=7.1Hz,
3H),1.07(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ188.85,
181.23,170.21,153.21,151.15,134.81,133.87,133.65,133.01,130.65,
128.99,129.78,128.66,127.32,126.87,126.60,125.88,125.14,123.12,
120.81,120.38,116.72,77.13,63.39,62.87,45.89,18.44,16.12,
15.77;31P NMR(202MHz,CDCl3)δ20.86;ESI–MS m/z:566.2(M–H)—;
Anal.Calc.(for C29H30NO9P):C,61.37;H,5.33;N,2.47;Found:C,61.40;
H,5.34;N,2.51.
Accordingly, it can be determined that gained orange solids i is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (3-methoxyphenyl) methyl } diethyl phosphonate, its knot
Structure formula is shown below:
Embodiment 10:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (2-methoxyphenyl) methyl } synthesis of diethyl phosphonate (j)
1) synthesis of α-O, O' diethylamino (2-methoxyphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with adjacent methoxy
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 8；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 5mL methanol, drips 0.1mmol catalyst 1-hydroxy benzo three under ice bath
Azoles, is stirred at room temperature 5min, is subsequently adding 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimmonium salt hydrochlorate, continues stirring 5min；1mmol α-O, O' diethyl is dripped again in this round-bottomed flask
Base amino (2-methoxyphenyl) methylphosphonic acid diethylester (dissolves with 5mL N,N-dimethylformamide and joins
Become solution, add in the way of solution), under the conditions of 35 DEG C, stirring reaction is to completely (about 4h), then to
Reactant liquor adds chloroform, washing, collected organic layer, organic layer with anhydrous sodium sulfate dried on
Silica gel column chromatography is with ethyl acetate: the mixed solvent eluting that petroleum ether=1:80 (volume ratio) forms, thin
Analyse tracing detection layer by layer, collect eluent, eluent solvent evaporated, obtain orange solids j.
Being analyzed gained orange solids j, its physics and chemistry and spectral characteristic are as follows:
Yields86.52%;1H NMR(500MHz,CDCl3)δ13.08(s,-OH,1H),
8.36–8.25(m,Ar-H,3H),8.02-7.84(m,Ar-H,4H),7.40(d,Ar-H,J
=7.2Hz,1H),7.33(t,Ar-H,J=7.8Hz,1H),7.00(t,Ar-H,J=7.4
Hz,1H),6.94(d,NH,J=8.2Hz,1H),5.96(dd,PCH,J=20.8,9.8
Hz,1H),4.96(dd,OCHCO,J=27.6,6.8Hz,1H),4.03–3.96(m,OCH2,
2H),3.97–3.76(m,OCH2,2H),3.91(s,OCH3,3H),1.67(d,CH3,J=
6.6Hz,3H),1.18(t,OCH3,J=7.0Hz,3H),1.09(t,OCH3,J=7.0Hz,
3H);13C NMR(125MHz,CDCl3)δ188.96,181.28,170.52,163.26,151.25,
135.67,134.93,133.97,133.72,133.05,129.72,129.61,127.41,127.01,
126.92,120.84,120.48,120.06,120.02,119.77,116.78,77.06,63.46,
63.02,50.43,18.55,16.16,16.05;31P NMR(202MHz,CDCl3)δ21.19;
ESI–MS m/z:566.2(M–H)—;Anal.Calc.(for C29H30NO9P):C,61.37;
H,5.33;N,2.47;Found:C,61.43;H,5.37;N,2.50.
Accordingly, it can be determined that gained orange solids j is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (2-methoxyphenyl) methyl } diethyl phosphonate, its knot
Structure formula is shown below:
Embodiment 11:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (phenyl) methyl } synthesis of diethyl phosphonate (k)
1) synthesis of α-O, O' diethylamino (phenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, use benzaldehyde
Replace p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 8；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 5mL methanol, drips 0.2mmol catalyst 1-hydroxy benzo three under ice bath
Azoles, is stirred at room temperature 10min, is subsequently adding 1.2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide hydrochloride, continues stirring 5min；1mmol α-O, O' bis-is dripped again in this round-bottomed flask
Ethylamino (phenyl) methylphosphonic acid diethylester, under room temperature condition, stirring reaction is to complete (about 4h), so
Adding chloroform in backward reactant liquor, washing, collected organic layer, organic layer anhydrous sodium sulfate is dried
Rear upper silica gel column chromatography, with ethyl acetate: the mixed solvent eluting that petroleum ether=1:60 (volume ratio) forms,
Thin layer chromatography tracing detection, collects eluent, eluent solvent evaporated, obtains orange solids k.
Being analyzed gained orange solids k, its physics and chemistry and spectral characteristic are as follows:
Yields88.16%;1H NMR(500MHz,CDCl3)δ13.04(s,-OH,1H),
8.33–8.28(m,Ar-H,2H),8.06–8.01(m,Ar-H,1H),7.85–7.78(m,Ar-H,
3H),7.47–7.03(m,Ar-H,5H,NH,1H),5.50(dd,PCH,J=20.7,9.6
Hz,1H),4.91(dd,OCHCO,J=32.3,6.8Hz,1H),3.97–3.69(m,OCH2,
4H),1.66(d,CH3,J=6.8Hz,3H),1.14(t,OCH3,J=7.0Hz,3H),1.05
(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ189.04,181.19,
170.48,153.43,151.36,135.01,134.03,133.81,133.14,131.80,130.45,
129.66,129.61,129.55,127.51,127.30,127.01,123.97,121.28,120.51,
116.95,77.36,63.42,63.06,49.77,18.56,16.21,16.15;31P NMR(202
MHz,Acetone)δ20.99;ESI–MS m/z:538.2(M+H)+;Anal.Calc.(for
C28H28NO8P):C,62.57;H,5.25;N,2.61;Found:C,62.53;H,5.27;N,
2.60.
Accordingly, it can be determined that gained orange solids k is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (phenyl) methyl } diethyl phosphonate, its structural formula is as follows
Shown in formula:
Embodiment 12:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (1-naphthyl) methyl } synthesis of diethyl phosphonate (l)
1) synthesis of α-O, O' diethylamino (1-naphthyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, by 1-naphthalene first
Aldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 8；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 15mL butanol, drips 0.5mmol catalyst 1-hydroxy benzo three under ice bath
Azoles, is stirred at room temperature 5min, is subsequently adding 1.3mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide hydrochloride, continues stirring 6min；1mmol α-O, O' bis-is dripped again in this round-bottomed flask
Ethylamino (1-naphthyl) methylphosphonic acid diethylester (dissolves wiring solution-forming with 5mL butanol, with the side of solution
Formula adds), under the conditions of 50 DEG C, stirring reaction is to completely (about 3.5h), then adds trichlorine in reactant liquor
Methane, washing, collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with second
Acetoacetic ester: the mixed solvent eluting that petroleum ether=1:40 (volume ratio) forms, thin layer chromatography tracing detection,
Collect eluent, eluent solvent evaporated, obtain orange solids l.
Being analyzed gained orange solids l, its physics and chemistry and spectral characteristic are as follows:
Yields89.14%;1H NMR(500MHz,CDCl3)δ13.05(s,-OH,1H),
8.33–8.20(m,Ar-H,3H),8.08(dd,Ar-H,J=9.4,3.1Hz,1H),
7.83–7.56(m,Ar-H,6H),7.57(dd,Ar-H,J=14.5,7.1Hz,1H),
7.53–7.45(m,Ar-H,2H),7.27(d,NH,J=9.3Hz,1H),6.39(dd,PCH,
J=20.8,9.6Hz,1H),4.91(dd,OCHCO,J=20.4,6.7Hz,1H),4.01–3.52
(m,OCH2,4H),1.62(d,CH3,J=6.7Hz,3H),1.18(t,OCH3,J=7.0
Hz,3H),0.85(t,OCH3,J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ188.97,
181.35,170.39,170.34,153.34,151.27,134.94,134.87,133.99,133.77,
130.77,129.11,129.03,128.78,128.54,127.44,126.99,126.73,126.00,
125.26,123.24,122.96,120.93,120.50,116.84,77.12,63.51,62.99,
46.01,18.56,16.24,15.89;31P NMR(202MHz,CDCl3)δ21.33;ESI–MS
m/z:586.2(M–H)—;Anal.Calc.(for C32H30NO8P):C,65.41;H,5.15;
N,2.38;Found:C,65.50;H,5.17;N,2.40.
Accordingly, it can be determined that gained orange solids l is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (1-naphthyl) methyl } diethyl phosphonate, its structural formula is such as
Shown in following formula:
Embodiment 13:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (4-methoxyphenyl) methyl } synthesis of diethyl phosphonate (m)
1) synthesis of α-O, O' diethylamino (4-methoxyphenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with to methoxy
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 8；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL dimethyl sulfoxide, drips 0.5mmol catalyst 1-hydroxyl under ice bath
Benzotriazole, is stirred at room temperature uniformly, is subsequently adding 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-
Ethyl-carbodiimide hydrochloride, stirs；1mmol α-O, O' bis-is dripped again in this round-bottomed flask
Ethylamino (4-methoxyphenyl) methylphosphonic acid diethylester, under the conditions of 60 DEG C, stirring reaction is to (the most about
3h), in reactant liquor, chloroform, washing, collected organic layer, organic layer anhydrous slufuric acid are then added
Sodium goes up silica gel column chromatography after drying, with ethyl acetate: the mixed solvent that petroleum ether=1:5 (volume ratio) forms
Eluting, thin layer chromatography tracing detection, collect eluent, eluent solvent evaporated, obtain orange solids m.
Being analyzed gained orange solids m, its physics and chemistry and spectral characteristic are as follows:
Yields84.82%;1H NMR(500MHz,CDCl3)δ12.99(s,-OH,1H),
8.30–8.21(m,Ar-H,2H),7.89–7.68(m,Ar-H,4H),7.42–7.20(m,Ar-H,
2H,NH,1H),6.80(dd,Ar-H,J=89.3,8.4Hz,2H),5.41(dd,PCH,J
=20.2,9.6Hz,1H),4.87(dd,OCHCO,J=12.3,5.3Hz,1H),4.15–3.80
(m,OCH2,4H),3.70(s,OCH3,3H),1.63(d,CH3,J=6.7Hz,3H),1.14
(t,OCH3,J=6.9Hz,3H),1.06(t,OCH3,J=7.0Hz,3H);13C NMR(125
MHz,CDCl3)δ188.91,181.20,170.26,159.46,153.33,151.25,134.88,
133.92,133.73,133.06,129.07,127.38,127.07,126.90,126.47,120.99,
120.43,116.80,114.11,113.90,77.25,63.21,62.77,55.20,49.84,
18.52,16.18,16.13;HRMS(m/z)(ESI):calcd for C29H30NO9P[M+H+]:
567.16852;found:567.16357;Anal.Calc.(for C29H30NO9P):C,61.37;H,
5.33;N,2.47;Found:C,61.40;H,5.35;N,2.45.
Accordingly, it can be determined that gained orange solids m is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (4-methoxyphenyl) methyl } diethyl phosphonate, its knot
Structure formula is:
Embodiment 14:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (3-aminomethyl phenyl) methyl } diethyl phosphonate (n)
1) synthesis of α-O, O' diethylamino (3-aminomethyl phenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with between methyl
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) in round-bottomed flask, 4.4mmol alizarin is dissolved in 25mL dimethyl sulfoxide, adds
4.4mmol2-bromo-propionic acid, adds 22mmol acid binding agent potassium hydroxide (in solid form add), 15 DEG C
Under the conditions of under room temperature condition stirring reaction to completely (about 2 days), in reactant liquor, then add ethyl acetate,
Washing, collects water layer, water layer phosphoric acid is adjusted to acidity (pH=6), has orange Precipitation, filters,
Collect precipitation, be washed to neutrality, be dried, obtain 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene
-2-base epoxide) propanoic acid；1H NMR(DMSO,500MHz):13.10(s,1H),8.29-8.16(m,
2H),7.99-7.89(m,2H),7.72(d,J=8.4Hz,1H),7.31(d,J=8.5Hz,
1H),5.09(q,J=6.8Hz,1H),1.60(d,J=6.8Hz,3H);FAB-MS m/z:
313[M+H]+;Anal.Calcd.C17H12O6:C,65.39;H,3.87.Found:C,65.43;
H,3.82.
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL dichloromethane, drips 0.2mmol catalyst 1-hydroxy benzenes under ice bath
And triazole, 5min is stirred at room temperature, is subsequently adding 1.7mmol condensing agent 1-(3-dimethylamino-propyl)-3-
Ethyl-carbodiimide hydrochloride, continues stirring 8min；1mmol α-O is dripped again in this round-bottomed flask,
O' diethylamino (3-aminomethyl phenyl) methylphosphonic acid diethylester (use 5mL dichloromethane wiring solution-forming, with
The mode of solution adds), under room temperature condition, stirring reaction is to completely (about 4h), then adds in reactant liquor
Entering chloroform, wash, collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate,
With ethyl acetate: the mixed solvent eluting that petroleum ether=1:8 (volume ratio) forms, thin layer chromatography tracing detection,
Collect eluent, eluent solvent evaporated, obtain orange solids n.
Being analyzed gained orange solids n, its physics and chemistry and spectral characteristic are as follows:
Yields87.32%;1H NMR(500MHz,CDCl3)δ12.97(s,-OH,1H),
8.31–8.23(m,Ar-H,2H),7.90(dd,Ar-H,J=9.6,4.1Hz,1H),
7.81–7.69(m,Ar-H,3H),7.27–7.23(m,Ar-H,2H),7.13–6.96(m,Ar-H,
2H,NH,1H),5.46(dd,PCH,J=9.7,5.3Hz,1H),4.82(dd,OCHCO,J
=12.2,5.5Hz,1H),4.17–3.70(m,OCH2,4H),2.20(s,CH3,3H),1.73
(d,CH3,J=6.8Hz,3H),1.32(t,OCH3,J=7.1Hz,3H),1.05(t,OCH3,
J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ188.94,181.22,170.45,
153.38,151.28,138.35,134.90,134.28,133.92,133.08,129.02,128.87,
128.43,127.41,127.10,126.92,124.88,121.05,120.84,120.49,116.83,
63.35,63.12,50.46,49.23,21.24,18.70,16.33,16.16;31P NMR(202
MHz,CDCl3)δ21.02;HRMS(m/z)(ESI):calcd for C29H30NO8P[M+H+]:
551.17090;found:551.16870;Anal.Calc.(for C29H30NO8P):C,63.15;H,
5.48;N,2.54;Found:C,63.20;H,5.47;N,2.50.
Accordingly, it can be determined that gained orange solids n is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (3-aminomethyl phenyl) methyl } diethyl phosphonate, its structure
Formula is shown below:
Embodiment 15:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (4-tolyl) methyl } synthesis of diethyl phosphonate (o)
1) synthesis of α-O, O' diethylamino (4-tolyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with to methyl
Benzaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 14；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL chloroform, drips 0.1mmol catalyst 1-hydroxy benzenes under ice bath
And triazole, it is stirred at room temperature uniformly, is subsequently adding 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl
Carbodiimide hydrochloride, stirs；1mmol α-O, O' diethyl is dripped again in this round-bottomed flask
Amino (4-tolyl) methylphosphonic acid diethylester is (with 10mL dimethyl sulfoxide wiring solution-forming, with solution
Mode adds), under the conditions of 20 DEG C, stirring reaction is to completely (about 4h), then adds trichlorine in reactant liquor
Methane, washing, collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with second
Acetoacetic ester: the mixed solvent eluting that petroleum ether=1:15 (volume ratio) forms, thin layer chromatography tracing detection,
Collect eluent, eluent solvent evaporated, obtain orange solids o.
Being analyzed gained orange solids o, its physics and chemistry and spectral characteristic are as follows:
Yields83.98%;1H NMR(500MHz,CDCl3)δ13.00(s,-OH,1H),
8.33–8.25(m,Ar-H,2H),7.87–7.69(m,Ar-H,4H),7.36–7.09(m,Ar-H,
4H, NH, 1H), 5.44 (dd, PCH, J=20.3,9.6Hz, 1H), 4.88 (dd, OCHCO,
J=6.8,1.2Hz,1H),4.14–3.69(m,OCH2,4H),2.33(s,CH3,3H),1.64
(d,CH3,J=6.8Hz,3H),1.14(t,OCH3,J=7.1Hz,3H),1.07(t,OCH3,
J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ188.95,181.25,170.27,
170.21,153.42,151.29,138.00,134.91,133.95,133.78,133.12,131.42,
129.39,127.71,127.67,127.42,127.14,126.94,121.09,120.45,116.86,
63.23,62.77,50.24,49.01,21.09,18.55,16.19,16.13;31P NMR(202
MHz,CDCl3)δ20.23;HRMS(m/z)(ESI):calcd for C29H30NO8P[M+H+]:
551.17090;found:551.16852;Anal.Calc.(for C29H30NO8P):C,63.15;H,
5.48;N,2.54;Found:C,63.21;H,5.53;N,2.58.
Accordingly, it can be determined that gained orange solids o is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (4-tolyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 16:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (3-fluorophenyl) methyl } synthesis of diethyl phosphonate (p)
1) synthesis of α-O, O' diethylamino (3-fluorophenyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, with between fluorobenzene
Formaldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 14；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 10mL methanol, drips 0.3mmol catalyst 1-hydroxy benzo three under ice bath
Azoles, is stirred at room temperature uniformly, is subsequently adding 1.6mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimmonium salt hydrochlorate, stirs；1mmol α-O, O' diethyl amino is dripped again in this round-bottomed flask
Base (3-fluorophenyl) methylphosphonic acid diethylester is (with 5mL dimethyl sulfoxide wiring solution-forming, in the way of solution
Add), under the conditions of 10 DEG C, stirring reaction is to completely (about 5h), then adds chloroform in reactant liquor,
Washing, collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with ethyl acetate:
The mixed solvent eluting that petroleum ether=1:15 (volume ratio) forms, thin layer chromatography tracing detection, collect eluting
Liquid, eluent solvent evaporated, obtain orange solids p.
Being analyzed gained orange solids p, its physics and chemistry and spectral characteristic are as follows:
Yields80.93%;1H NMR(500MHz,CDCl3)δ13.02(s,-OH,1H),
8.34–8.28(m,Ar-H,2H),7.96(dd,Ar-H,J=9.3,4.7Hz,1H),
7.85–7.74(m,Ar-H,3H),7.38–7.24(m,Ar-H,2H),7.21–7.11(m,Ar-H,
2H),7.03–6.94(m,NH,1H),5.49(dd,PCH,J=9.5,5.1Hz,1H),4.90
(dd,OCHCO,J=32.1,6.3Hz,1H),4.16–3.80(m,OCH2,4H),1.74(d,
CH3,J=6.8Hz,3H),1.32(t,OCH3,J=7.1Hz,3H),1.09(t,OCH3,
J=7.1Hz,3H);13C NMR(125MHz,CDCl3)δ189.07,189.01,181.24,
170.62,153.19,151.23,137.02,134.98,134.02,133.99,133.81,133.13,
130.28,127.48,126.98,123.56,121.34,120.54,116.95,115.17,114.98,
77.26,63.50,63.12,50.18,18.66,16.39,16.21;31P NMR(202MHz,CDCl3)
δ20.93;HRMS(m/z)(ESI):calcd for C28H27FNO8P[M+H+]:555.14583;
found:555.14386;Anal.Calc.(for C28H27FNO8P):C,60.54;H,4.90;N,
2.52;Found:C,60.56;H,4.92;N,2.54.
Accordingly, it can be determined that gained orange solids p is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (3-fluorophenyl) methyl } diethyl phosphonate, its structural formula
It is shown below:
Embodiment 17:O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-oxygen
Methyl) propionamido] (2-naphthyl) methyl } synthesis of diethyl phosphonate (q)
1) synthesis of α-O, O' diethylamino (2-naphthyl) methylphosphonic acid diethylester
As step 1 in embodiment 1) described in method and condition synthesize, except for the difference that, by 2-naphthalene first
Aldehyde replaces p-bromobenzaldehyde.
2) synthesis of target product:
2.1) with embodiment 14；
2.2) in round-bottomed flask, by 1mmol2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-
Base epoxide) propanoic acid is dissolved in 5mL methanol, drips 0.1mmol catalyst 1-hydroxy benzo three under ice bath
Azoles, is stirred at room temperature uniformly, is subsequently adding 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl carbon
Diimmonium salt hydrochlorate, stirs；1mmol α-O, O' diethyl amino is dripped again in this round-bottomed flask
Base (2-naphthyl) methylphosphonic acid diethylester (with 5mL dimethyl sulfoxide wiring solution-forming, adds in the way of solution
Enter), under room temperature condition, stirring reaction is to completely (about 4h), then adds chloroform in reactant liquor,
Washing, collected organic layer, organic layer goes up silica gel column chromatography after drying with anhydrous sodium sulfate, with ethyl acetate:
The mixed solvent eluting that petroleum ether=1:15 (volume ratio) forms, thin layer chromatography tracing detection, collect eluting
Liquid, eluent solvent evaporated, obtain orange solids q.
Being analyzed gained orange solids q, its physics and chemistry and spectral characteristic are as follows:
Yields85.62%;1H NMR(500MHz,CDCl3)δ13.09(s,-OH,1H),8.32
(dd,Ar-H,J=6.6,4.4Hz,2H),8.11(dd,Ar-H,J=9.5,4.0Hz,1H),
7.93–7.81(m,Ar-H,6H),7.65(d,Ar-H,J=8.3Hz,1H),7.58(d,Ar-H,
J=8.6Hz,1H),7.51–7.47(m,Ar-H,2H),7.30(d,NH,J=8.5Hz,
1H),5.66(dd,PCH,J=20.7,9.5Hz,1H),4.90(dd,OCHCO,J=28.2,
6.7Hz,1H),4.21–3.62(m,OCH2,4H),1.66(d,CH3,J=6.7Hz,3H),
1.16(t,OCH3,J=7.0Hz,3H),1.03(t,OCH3,J=7.0Hz,3H);13C NMR
(125MHz,CDCl3)δ189.09,183.36,181.40,157.80,153.43,135.05,
134.09,133.18,132.95,131.78,128.66,128.19,128.11,127.96,127.71,
127.55,127.40,127.06,126.47,125.48,123.84,121.15,120.87,120.61,
81.21,77.32,63.62,63.30,49.52,18.67,17.83,16.27;31P NMR(202
MHz,CDCl3)δ20.90;ESI–MS m/z:586.2(M–H)—;Anal.Calc.(for
C32H30NO8P):C,65.41;H,5.15;N,2.38;Found:C,65.45;H,5.20;N,
2.42.
Accordingly, it can be determined that gained orange solids q is O, O' diethyl { [2-(1-hydroxyl-9,10-dioxo
-9,10-dihydroanthracene-2-oxygen methyl) propionamido] (2-naphthyl) methyl } diethyl phosphonate, its structural formula is such as
Shown in following formula:
In order to the alizarin aminophosphonate ester derivatives of the present invention purposes in pharmacy, applicant couple are described
The compound that above-described embodiment 1～17 prepares has carried out anti-tumor activity experiment.
With the anti-tumor medicine 5-fluorouracil of Clinical practice as positive control drug, make the moon with coordinative solvent
Property comparison, with HCT-116(human colon cancer cell), MGC-803 (lung carcinoma cell), NCI(lung carcinoma cell),
A549 (lung carcinoma cell), KB (oral cavity epidermoid carcinoma cell) are subject cell strain；With mtt assay to compound
Carry out anti tumor activity in vitro test.
By medicine and co-culture of cells 48h, according to the result of preliminary experiment cell growth rate, inoculation is certain
The cell 190 μ L of density is in 96 well culture plates (about 5 × 104～1 × 105Individual/hole).
24h is after cell attachment in cultivation, is separately added into the sample 10 μ L of series concentration, each sample
If 5 multiple holes, wherein ethanol final concentration ＜ 1%. separately sets negative control hole 4, adds 10 μ L blank
Substrate.
Cell is in saturated humidity, 5%CO2, hatch the every hole of 48h. under the conditions of 37 DEG C and add 10 μ L MTT
(5mg/ml), continue to cultivate 4h.
Suck supernatant, add DMSO150 μ L/ hole, after fully dissolving, measure wavelength by microplate reader
For 570nm with reference to measuring OD value at 630nm, calculate each dosing holes cell proliferation inhibition rate, knot
Fruit is as described in Table 1.
Table 1 compound IC to different cell strains50Value
As can be seen from the table, the anti tumor activity in vitro of alizarin itself is the highest, but most of alizarin ammonia
The cytotoxicity of base phosphate derivatives is the most significantly higher than the activity of alizarin.Thin for people's pulmonary carcinoma NCI
Born of the same parents, most derivant shows preferable anti tumor activity in vitro, if compound e and h is to NCI cell
It is provided with higher activity (IC50Value is all 3.80 μMs), exceed the medicine five fluorine urine of clinical anticancer
Pyrimidine.For oral cavity epidermoid carcinoma KB cell, it is phonetic that the activity of most of derivants is above medicine five fluorine urine
Pyridine.
In order to verify the above-mentioned all compounds cytotoxicity to human normal cell further, we utilize
Mtt assay is to human venous endothelial cell HUVEC(normal cell) carry out screening active ingredients, result shows institute
There is the IC of compound50It is worth the IC of all comparison tumor cells50Value is big, say, that all derivants are normal to people
The toxicity of cell is less than the toxicity of these compound on tumor cells.
Being shown by above-mentioned anti tumor activity in vitro testing experiment, alizarin amido phosphonate of the present invention spreads out
Biology, can strengthen the anti-tumor activity of alizarin self to a great extent, be expected to be used for antitumor drug
Preparation.
Claims (7)
1. the synthetic method of alizarin aminophosphonate ester derivatives, comprises the following steps:
1) with alizarin and 2 bromopropionic acid as raw material, it is dissolved in polar solvent, at acid binding agent potassium hydroxide
React under conditions of existence to completely, in reactant liquor, add ethyl acetate, washing, collect water layer,
Water layer is adjusted to acidity, has Precipitation, filter, collect precipitation, be dried, obtain 2-(1-hydroxyl
-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid；
2) with 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid and α-
Amido phosphonate is raw material, is dissolved in polar solvent, at catalyst I-hydroxybenzotriazole and condensing agent
1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride reacts to completely under conditions of existing；
Adding chloroform in reactant liquor, washing, collected organic layer, upper silica gel column chromatography, with by volume
The mixed solvent eluting formed than ethyl acetate and the petroleum ether for 1:4～100, eluent is evaporated molten
Agent, i.e. obtains corresponding alizarin aminophosphonate ester derivatives；
Shown in the general structure such as following formula (I) of described alizarin aminophosphonate ester derivatives:
Wherein, R be p-bromophenyl, o-bromophenyl, a bromophenyl, to fluorophenyl, adjacent fluorophenyl,
Rubigan, a chlorphenyl, Chloro-O-Phenyl, m-methoxyphenyl, o-methoxyphenyl, phenyl,
1-naphthyl, p-methoxyphenyl, an aminomethyl phenyl, p-methylphenyl, a fluorophenyl or 2-naphthyl.
The synthetic method of alizarin aminophosphonate ester derivatives the most according to claim 1, its feature
It is: step 2) in, described α-aminophosphonicacid ester is:
α-O, O' diethylamino (4-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-bromophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-fluorophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-fluorophenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-chlorphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (2-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (phenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (1-naphthyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-methoxyphenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-aminomethyl phenyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (4-tolyl) methylphosphonic acid diethylester；
α-O, O' diethylamino (3-fluorophenyl) methylphosphonic acid diethylester；Or
α-O, O' diethylamino (2-naphthyl) methylphosphonic acid diethylester.
The synthetic method of alizarin aminophosphonate ester derivatives the most according to claim 1, its feature
It is: step 1) and 2) in, described polar solvent is selected from dimethyl sulfoxide, N, N-dimethyl
In Methanamide, ethyl acetate, methanol, ethanol, propanol, butanol, dichloromethane and chloroform
Or the most two or more a kind of combinations.
4. according to the synthesis side of alizarin aminophosphonate ester derivatives according to any one of claims 1 to 3
Method, it is characterised in that: step 1) in, the addition of described acid binding agent potassium hydroxide is alizarin material
3～5 times of amount.
5. according to the synthesis side of alizarin aminophosphonate ester derivatives according to any one of claims 1 to 3
Method, it is characterised in that: step 1) in, the temperature of described reaction is less than 50 DEG C.
6. according to the synthesis side of alizarin aminophosphonate ester derivatives according to any one of claims 1 to 3
Method, it is characterised in that: step 2) in, the addition of described catalyst I-hydroxybenzotriazole is 2-
The amount of (1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid material 0.05～
0.5 times；The addition of described condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
The amount that amount is 2-(1-hydroxyl-9,10-dioxo-9,10-dihydroanthracene-2-base epoxide) propanoic acid material
1～2 times.
7. according to the synthesis side of alizarin aminophosphonate ester derivatives according to any one of claims 1 to 3
Method, it is characterised in that: step 2) in, the temperature of described reaction is less than 80 DEG C.
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